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Pentapeptide Repeat Proteins
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This entry is adapted from the peer-reviewed paper 10.3390/biom11050638

The pentapeptide repeat protein (PRP) superfamily, identified in 1998, has grown to nearly 39,000 sequences from over 3300 species. PRPs, recognized as having at least eight contiguous pentapeptide repeats (PRs) of a consensus pentapeptide sequence, adopt a remarkable structure, namely, a right-handed quadrilateral β-helix with four consecutive PRs forming a single β-helix coil. Adjacent coils join together to form a β-helix “tower” stabilized by β-ladders on the tower faces and type I, type II, or type IV β-turns facilitating an approximately −90° redirection of the polypeptide chain joining one coil face to the next. PRPs have been found in all branches of life, but they are predominantly found in cyanobacteria. Cyanobacteria have existed on earth for more than two billion years and are thought to be responsible for oxygenation of the earth’s atmosphere. Filamentous cyanobacteria such as Nostoc sp. strain PCC 7120 may also represent the oldest and simplest multicellular organisms known to undergo cell differentiation on earth.

Pentapeptide Repeat Proteins cyanobacteria filamentous cyanobacteria

1. Background

The first description of a pentapeptide repeat protein (PRP) was reported in 1995, when Haselkorn and coworkers identified a gene from the filamentous cyanobacterium Nostoc (formerly Anabaena) sp. strain PCC 7120, which, when mutated, altered the composition of glycolipids encasing the heterocysts, among other alterations (Figure 1) [1]. They named the gene heterocyst-specific glycolipids-directing protein K (hglK) for the role that the gene played in localization of glycolipids to heterocysts. The protein encoded by the hglK gene, HglK, was predicted to contain four trans-membrane spanning regions and an unusual alanine- and leucine-rich pentapeptide repeat (PR) region made up of 36 PRs with the consensus sequence AXLXX [1]. Therefore, HglK was the first PRP to be associated with a putative biochemical function. To date, however, the precise mechanism for the role that HglK plays in regulating glycolipid localization to heterocysts remains unknown.
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Figure 1. Milestones in the timeline investigation of the structure and function of PRPs.
In 1998, Bateman et al. [2] reported the discovery of a novel family of proteins, to which HglK belonged, that contained tandem PRs with the sequence motif A(D/N)LXX, based on the analysis of recently determined complete genomes of several bacteria at the time. They observed that PRPs were most commonly found in cyanobacteria [2]. The authors also proposed a model of PRP structures, rightly predicting that PRPs would adopt a right-handed β helical architecture; however, they predicted a triangular-shaped helix, which would prove to be in error once the first three-dimensional structures of PRPs were determined several years later.
Furthermore, in 1998, Martínez-Martínez confirmed that quinoline resistance in bacteria could be carried on a multi-resistance plasmid (pMG252), which they discovered in a clinical isolate of Klebsiella pneumonia [3]. Bacterial acquisition of antimicrobial resistance undergoes constant evolution with horizontal gene transfer through plasmids playing a major role [4]. In 2001, Montero et al. discovered that intrinsic resistance to fluoroquinolines was influenced by MfpA, a putative PRP-containing protein encoded by a chromosomal gene in Mycobacterium smegmatis [5]. In 2005, Hegde et al. [6] solved the three-dimensional structure of MfpA from Mycobacterium tuberculosis, a homologue of MfpA from M. smegmatis, representing the first three-dimensional structure of a PRP, revealing that it adopted a right-handed quadrilateral β helical structure. Hegde et al. also reported that the structure and electrostatic charge distribution of MfpA mimicked that of DNA, and therefore MfpA was able to confer fluoroquinoline resistance to M. tuberculosis due to its ability to mimic DNA, bind to DNA gyrase and inhibit its function [6]. Soon after, many more chromosomal genes encoding homologs of MfpA were discovered in the genomes of a variety of organisms and in 2013, Jacoby and Hooper reported a phylogenetic tree analysis that showed that quinoline resistance genes (qnr) and mfpA homologs could be identified in the chromosomes of 58 Gram-negative bacteria and 34 Gram-positive organisms and in 14 plasmid-mediated genes [7].
In 2003, Chandler et al. [8] ascribed a cellular function to RfrA, a PRP from the cyanobacterium Synechocystis 6803, showing that it played a role in regulating a novel manganese uptake system; however, the nature of the system and the precise role that RfrA plays in regulating the manganese uptake system remains unknown.
By 2006, Vetting et al. [9] reported that the PRP family had grown to more than 500 members in the prokaryotic and eukaryotic kingdoms and they updated the PR consensus sequence as [S,T,A,V][D,N][L,F][S,T,R][G]. In 2009, Buchko reviewed the knowledge of the structure and function of PRPs from cyanobacteria [10]. In 2014, Shah and Heddle reported that a query of the Pfam database (http://pfam.xfam.org (accessed on 15 June 2014)) for members of the PR family (PF00805) had expanded to 11,082 sequences from 1513 species [11] and that protein structures had been solved for a number of PRPs from Nostoc. sp. PCC 7120 [12][13], Cyanothece 51142 [14][15], Arabidopsis thaliana [16], Enterococcus faecalis [17], K. pneumonia [18], Xanthomonas albilineans [19], Aeromonas hydrophila [20], and M. tuberculosis [6]. In 2019, Zhang et al. updated the PR consensus sequence to (A/C/S/V/T/L/I)/(D/N/S/K/E/I/R)/(L/F)/(S/T/R/E/Q/K/V/D)/(G/D/E/N/R/Q/K) based on the consideration of several newly available PRP crystal structures [21]. By 2020, the number of PRPs in the PF00805 Pfam had increased to 38,000 sequences in over 3300 species reported in a study by Xu and Kennedy that characterized the protein dynamics in PRPs [22]. The current distribution of PRPs in PF00805 Pfam is depicted in Figure 2, indicating 38,981 PRP sequences distributed over 3338 species (https://pfam.xfam.org/family/PF00805#tabview=tab7 (accessed on 25 April 2021)). In this sunburst plot, 82.2% of the species and 84.7% of the sequences belong to bacteria, 14.1% of species and 13.7% of sequences belong to eukaryota, 0.5% of species and 1.4% of sequences belong to viruses, and 1.1% of species and 2.2% of sequences belong to archaea. The plot shows that PRPs are found most abundantly in cyanobacteria, with 26.9% of all PRP sequences occurring in cyanobacteria; however, cyanobacteria represent only 3.7% of the species in which PRPs have been discovered, indicating that PRPs likely played an important physiological or structural role in the evolution and lifecycle of ancient cyanobacteria. Despite the large and growing nature of the PRP superfamily, three-dimensional structures of only sixteen PRP or PRP-containing proteins have been determined, thirteen of which contain a single PRP domain with α helices capping the N and/or C termini and three of which contain two or more domains including the PRP domain.
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Figure 2. Distribution of PRP sequences across species. This sunburst plot of the PF00805 PRP Pfam shows the distribution of 38,981 sequences across 3338 species. The color-coding in the sunburst plot is indicated in the legend.
Ranging from those that have putative associated biochemical or cellular functions to those that have had structures determined but with unknown putative functions, including those involved in (1) heterocyst glycolipid synthesis, (2) manganese uptake, (3) gyrase inhibition, (4) ubiquitin E3 ligases, (5) synaptic vesicle glycoprotein 2 isoform C (SV2C) receptors, and (6) plant and cyanobacteria proteins with three-dimensional structures but no functional characterization (Figure 3). Although the biological functions of most PRPs remain unknown, three-dimensional structures of PRPs and PRP-containing multidomain proteins continue to be solved and reported with the hope of helping to eventually understand their biological, biochemical or cellular functions.
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Figure 3. Summary of the PRPs discussed with and without known three-dimensional structures. The six category groups are shown in the first branch. The second and subsequent branches indicate specific PRPs. PRPs with known structures include the corresponding PDB ID inside parentheses immediately to the right of the PRP name.

2. Cyanobacterial and Eubacterial PRPs with an Associated Biochemical or Cellular Function

2.1. Heterocyst Glycolipid Biosynthesis-HglK

In 1995, Haselkorn and coworkers identified the hglK gene in mutant strain 543 of the filamentous Nostoc sp. strain PCC 7120 [1]. The mutant strain was isolated as a Fox− (lack of ability to fix dinitrogen except in an oxygen-depleted environment) mutant [23] following chemical mutagenesis [24]. The ultrastructural phenotype of the mutant strain showed that, in nitrogen replete media, i.e., media containing an abundant usable soluble nitrogen source, the vegetative cells in the filaments, i.e., those cells capable of dividing and extending the filament length, were more cylindrical and had thicker septa compared to the wild-type strain, whereas in nitrogen depleted media, the mutant heterocysts lacked the glycolipid layer that is normally exterior to the cell wall and isolates the nitrogenase enzyme that is required for fixation of atmospheric nitrogen inside the heterocysts from oxygen that inactivates the nitrogenase enzyme. Hydropathy analysis indicated that the 727 amino acid HglK protein contained four potential trans-membrane regions in its N-terminal region and 36 PRs in its C-terminal region starting at amino acid position 501. Analysis of the mutant strain indicated that it contained a stop codon just upstream of the DNA encoding the PRP domain. Because heterocysts in the mutant strain lacked the glycolipid layer exterior to the cell wall, the authors used thin-layer chromatography to analyze the lipid content of the mutant and wild-type strains and found no difference. The authors therefore concluded that the hglK gene encoded a protein that was necessary for localization of glycolipids to the heterocyst walls and that this function required the PRP domains.
Ar é valo and Flores further characterized the function of the hglK gene and discovered that hglK mutants were also defective in heterocyst differentiation, being impaired in the expression of the heterocyst-related genes coxB2A2C2 (a cytochrome c oxidase) and nifHDK (a nitrogenase) [25]. The authors also observed that HglK was predominantly localized at the intercellular septa and was required for biogenesis of long filaments, to produce normal numbers of nanopores, and for normal intercellular molecular transfer activity. The authors concluded that HglK contributed to the architecture of the intercellular septa and impacted the function of septal junctions [25]. The precise biochemical role of HglK remains unknown and no three-dimensional structure of HglK is currently available.

2.2. Regulator of Manganese Uptake-RfrA

In 2003, Pakrasi and coworkers discovered that RfrA (gene name sll1350), a PRP from Synechocystis 6803, was a regulator of a novel high-affinity manganese uptake system [8]. RfrA and its function were identified in a suppressor screen in which the mutant strain was deficient in both mntC, a gene encoding a component of an ABC transport system for manganese, and psbO, which encoded an extrinsic manganese stabilizing protein of photosystem II. In a suppressor screen, one looks for additional mutations that reverse the mutant phenotype, in this case, deficiency in manganese transport. The authors discovered that a point mutation in rfrA restored photosynthetic activity of the ΔmntC, ΔpsbO double deletion mutant. Radioactive manganese uptake experiments indicated that RfrA was a regulator of a high affinity manganese transport system that was different from the known manganese ABC transport system. The authors named the 398 amino acid RfrA protein for the repeat five-residues (Rfr) domain, which is another name for PRPs, which occurred in the N-terminus of the protein. Genetic analysis indicated that Synechocystis 6803 contained sixteen PRPs. RfrA was the first member of the PRP family to be linked to a specific physiological process. RfrA has no sequence or structural similarities to previously described bacterial manganese transcription factors and it does not have any known DNA-binding domains [26]. It has been postulated that RfrA may regulate the second manganese transporter through a mechanism other than transcriptional control, such as by reversible protein modifications at the post-translational level [26]. Despite the link to regulation of manganese uptake, the nature of the hypothetical second high-affinity manganese importer, its regulatory mechanism, and the precise biochemical role that RfrA plays regulating the putative manganese transporter remains unknown [26]. The three-dimensional structure of RfrA also remains unknown.

2.3. Gyrase Inhibitors

2.3.1. MfpA (2BM4, 2BM5, 2BM6 and 2BM7)

In the early 2000s, with the growing antibiotic resistance of M. tuberculosis to two bactericidal compounds, isoniazid and rifampicin [27], fluoroquinolines had become the most common new antibiotic therapy to treat M. tuberculosis infections [6][27]. In 2001, Montero et al. identified a gene mfpA that encoded a PRP that conferred a new mechanism of fluoroquinoline resistance to M. smegmatis [5]. The protein encoded by the mfpA gene resulted in a low level of resistance to ciprofloxacin and sparfloxacine [5]. Hegde et al. [6] identified a 183-amino acid MfpA homolog from M. tuberculosis (MtMfpA) encoded by the Rv3361c gene that was 67% identical to the 192-residue M. smegmatis MfpA protein. In 2005, Hegde et al. [6] reported the three-dimensional structure of MfpA from M. tuberculosis revealing it to be a PRP made up of eight complete PR coils composed of a mixture of type II and type IV β turns (Figure 4). MfpA was the first PRP to have its three-dimensional structure solved. Hegde et al. reported that MfpA expression in vivo conferred resistance to the antibiotic fluoroquinolone. Fluoroquinolines are chemotherapeutic bactericidal drugs that interfere with DNA replication in bacteria, leading to bacterial cell death. Fluoroquinolines exert their antibacterial activity by interfering with the normal function of the type II topoisomerases, DNA gyrase and DNA topoisomerase IV. These enzymes normally cut the genomic DNA to allow supercoiling and then ligate the DNA to stabilize the supercoiled DNA. Fluoroquinoline acts by inhibiting the ligase activity of these enzymes and leaving the nuclease activity intact, resulting in accumulation of single- and double-strand breaks that leads to disrupted DNA replication and cell death. Fluoroquinoline acts by binding reversibly to the gyrase-DNA complexes and stabilizing the covalent enzyme tyrosyl-DNA phosphate ester that is normally a transient intermediate in the topoisomerase reaction. Hegde et al. reported that the three-dimensional structure of MfpA exhibited a size, shape and electrostatic surface similar to that of B-form DNA, and concluded that its mechanism of action was due to DNA mimicry [6]. Since fluoroquinoline only binds to DNA gyrase-DNA complexes, binding of MfpA to DNA gyrase blocks fluoroquinoline binding to DNA gyrase-DNA complexes, thus interfering with the bactericidal activity of fluoroquinoline [6].
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Figure 4. Structure and analysis of MfpA. The top panel (at left) shows the ribbon diagrams looking at the four different faces of the Rfr coil the structure and the corresponding electronic potential surface analysis (at right). The bottom panel shows the head-to-head dimer interface with non-bonded interactions depicted by yellow lines as identified using Intersurf [28] and depicted using Chimera [29]. Chain A is colored orange, Chain B is colored cyan, and interacting residues are labeled.
Because its function relies on a mechanism of DNA mimicry, MfpA exists as functional dimer. Two molecules of MfpA undergo a head-to-head interaction mediated by two α helices at the C terminus of each molecule to form an asymmetric rod-like shape with a hydrophobic dimer interface (Figure 4, top panel). Based on the electrostatic surface potential of the MfpA dimer, Hegde et al. generated a model in which the β helices of the MfpA dimer interacted with N terminal region of gyrase dimer through electrostatic interactions. The secondary structure of MfpA contains a β bulge in its β helix and two α helices at the C terminus and 28 to 29 β turns (Figure 4, top panel).
The head-to-head interaction two molecules of MfpA involves 81 contacts mediated by 18 residues on one chain and 17 residues on the second chain that interact through hydrogen bonds and non-bonded contacts involving a surface area of about 1700 Å2 (Figure 4, bottom panel). An interweaved interaction between two MfpA molecules is mediated by a short parallel β sheet involving residues 162–164 on one strand (chain A) and residues 178–181 on the second strand (chain B), an orthogonal interaction between α-helices (165–176 on each MfpA molecule), and another short parallel β sheet involving residues 178–181 (chain A) and 162–164 (chain B) (Figure 4, bottom panel). The dimer interaction was stabilized by a hydrophobic core formed by the interacting hydrophobic side chains from each α-helix primarily involving F172 (12 interactions), H176 (2 interactions), L178 (9 interactions), plus the H-bonds stabilizing the parallel β-sheets, and multiple interactions involving R145 (six interactions), R164 (7 interactions), and C179 (7 interactions) (Figure 4, bottom panel). The energy to form the dimer interaction was −15.8 kcal/mole (2BM4). Considering, that a single hydrogen-bond has a typical energy of 1–3 kcal/mol, this indicates that the head-to-head dimer formation is energetically favored (Figure 4, bottom panel).

2.3.2. EfsQnr (2W7Z)

In 2007, Arsene and Leclercq discovered a qnr-like gene from E. faecalis, EfsQnr, which conferred fluoroquinoline resistance to E. faecalis indicating that EfsQnr likely functioned as a DNA-gyrase inhibitor [30]. In 2009, Vetting et al. determined the three-dimensional structure of EfsQnr [17] revealing that the 211-residue protein was a PRP made up of eight complete Rfr coils composed of a mixture of type II and type IV β turns and a 12-residue C-terminal α helix capping the β helix. Two molecules of EfsQnr formed a head-to-head dimer mediated by an interaction between the C-terminal α helix of each EfsQnr molecule (Figure 5, top panel) similar to that observed in the structure of MfpA. Despite their structural similarity, a pairwise sequence alignment using EMBOSS Needle (https://www.ebi.ac.uk/Tools/psa/emboss_needle/ (accessed on 25 April 2021)) between EfsQnr and MfpA over 234 residues indicated just 19.7% sequence identity, 29.5% similarity, and 30.3% gaps. The head-to-head dimer interaction in EfsQnr involved 16 residues on one chain (chain A) and 15 residues on a second chain (chain B) involving 69 contacts encompassing an interface area of 1568 Å2. The head-to-head interaction was mediated similarly to in MfpA, involving interactions between parallel regions of the polypeptide backbone (residues 190–194 on chain A and 207–210 on chain B), interactions of the sidechains of the orthogonally oriented α-helices from each chain (residues 195–206 on each chain), and backbone and sidechain interactions from another short section of parallel polypeptide chains (residues 207–211 on chain A and residues 191–194 on chain B) (Figure 5, bottom panel). The hydrophobic interactions between the α-helices and adjacent strands were established by all hydrophobic, non-aromatic residues, including V94 (5 interactions), P196 (10 interactions), I200 (6 interactions), V209 (7 interactions), and I210 (7 interactions) and T211 (7 interactions) (Figure 5, bottom panel). The binding energy of the head-to-head dimer interaction was −14.9 kcal/mole, which was slightly weaker than in MfpA, that involved more residue interactions and a hydrophobic core involving aromatic side chains.
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Figure 5. Structure and analysis of EfsQnr. The top panel shows the ribbon diagrams of the structure for four different orientations (at left) and the corresponding electronic potential surface plots (at right). The bottom panel is the interface model calculated by Intersurf and depicted using Chimera.

2.3.3. QnrB1 (2XTW, 2XTX, and 2XTY)

QnrB1, encoded by multi-resistance plasmids [3][31] in isolates of Enterobacteriaceae from around the world [32], is a PRP that confers moderate fluoroquinoline resistance to its host organisms. Genes encoding QnrB1 can also be found on bacterial chromosomes [32]. QnrB1 belongs to the qnrB subfamily of Qnr genes that include qnrA [3], qnrB [33][34], qnrC [35], qnrD [36], qnrE [37], qnrS [38], and qnrVC [39][40] subfamilies [41].
The three-dimensional structure of QnrB1 from K. pneumoniae was determined by Vetting et al. in 2011 [18]. The 226-residue protein contained nine Rfr coils composed of a mixture of type II and type IV β turns, a 12-residue α helix capping its C terminus (D197–L208) and two loops projecting outward from the Rfr coil (an 8-residue loop (Loop A: Y46-G53) in coil 2 connecting face 2 to face 3 and projecting outward from face 2, and a 12-residue loop (Loop B: S102–S113) that projects outward from the corner between face 4 and face 1 joining coil 4 and col 5) (Figure 6, top panel). The head-to-head dimer was established by the interaction of the C-terminal helix of two QnrB1 molecules mediated by 40 non-bonded contacts involving 23 residues (chain A: 13 residues and chain D: 10 residues) for the interaction between chain A and chain D and 28 residues between chain B and chain C (chain B: 14 and chain C: 14) for the two dimers observed in the crystallographic asymmetric unit. The hydrophobic core was established by interactions between non-aromatic sidechains from each α helix, including I186 (five interactions), M205 (eight interactions), and I210 (eight interactions) (Figure 6, bottom panel). The interface between the A and D chains had an area of 1131 Å2, whereas the interface between the B and C chains had an area of 1432 Å2. Despite the rather large difference between the interface areas, the interaction energies between two dimers composed of different pairs of chains in the asymmetric unit were quite similar with an average of −10.6 kcal/mole. The dimer interface in QnrB1 involved fewer residues (23) and fewer contacts (40) and weaker binding (−10.6 kcal/mole) compared to MfpA (35 residues, 81 contacts and −15.8 kcal/mole) and EfsQnr (31 residues, 69 contacts and −14.9 kcal/mole). The authors noted potentially interestingly positioned residues in the two loops that were also conserved, indicating that they may define a possible contact surface with topoisomerases to assist binding with gyrase in addition to the guiding electrostatic interactions [18]. The authors also pointed out that deletion of the smaller loop affected gyrase inhibition while loss of the larger loop resulted in total inability to inhibit gyrase [18].
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Figure 6. Structure and analysis of QnrB1. The top panel shows the ribbon diagrams of the structure for four different orientations (at left) and the corresponding electronic potential surface plots (at right). The bottom panel is the interface model calculated by Intersurf and depicted using Chimera.
In 2019, Li et al. showed that QnrB increased bacterial mutation rates and the selection of quinolone-resistant mutants [33]. Transcriptomic and whole genome sequencing analysis indicated that QnrB upregulated gene expression and increased the number of gene copies near the origin of replication in both E. coli and K. pneumoniae [33]. The authors also reported that Bacterial two-hybrid and in vitro pull-down assays indicated that QnrB interacted with the DNA replication initiator DnaA [33].

2.3.4. AhQnr (3PSS and 3PSZ)

Xiong et al. reported the structure of AhQnr, a Qnr-like protein from A. hydrophila in, 2011 [20]. AhQnr adopted a Rfr fold with nine complete coils composed of a mixture of type II and type IV β turns capped by a 10-residue α-helix (D101-I210) and two conserved loops (Loop A (F47-C56) and Loop B (F103-C114) (Figure 7, top panel). The overall structure of AhQnr was very similar to that of QnrB1, consistent with the 38.8% sequence identity plus 56% similarity. The dimer interaction between two AhQnr chains involved a common motif with a short parallel β-sheet formed by residues Q197-N199 of chain A with I213-F215 of chain B, sidechain interactions between the two orthogonally-oriented α-helixes from each molecule, and a final short parallel β-sheet formed by L212-F215 of chain A with Q197-N199 of chain B with the interaction mediated by 96 contacts involving 20 residues on chain A and 20 residues on chain B. Interestingly, the dimer interaction was established by an equal mixture of polar residues and eight hydrophobic residues, with Q23 and F215 making the largest numbers of contacts at 11 and 12 interactions, respectively (Figure 7 bottom panel). The number of residues establishing the dimer interface in AhQnr (40) was greater than in MfpA (35), EfsQnr (31), and QnrB1 (23) and, correspondingly, the interface area of AhQNr (2039 Å2) was significantly larger than that of MfpA (1700 Å2), EfsQnr (1568 Å2) and QnrB1 (1131–1432 Å2). Interestingly, despite having the largest interface area, the energy of the AhQNr dimer interaction was the weakest of those discussed so far at −9.9 kcal/mole, compared to MfpA (−15.8 kcal/mole), EfsQnr (−14.9 kcal/mole), and QnrB1 (−10.6 kcal/mole). It is possible that more interactions were required to compensate for a less stable hydrophobic core, with the aromatic sidechain involved in the largest number of contacts, F215, residing on the surface of the protein and not participating in formation of a hydrophobic core.
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Figure 7. Structure and analysis of AhQnr. The top panel shows the ribbon diagrams of the structure for four different orientations (at left) and the corresponding electronic potential surface plots (at right). The bottom panel is the interface model calculated by Intersurf and depicted using Chimera.

2.3.5. AlbG (2XT2 and 2XT4)

AlbG is a self-resistance factor from X. albilineans against albicidin, a nonribosomally-encoded hybrid polyketide-peptide with antibiotic and phytotoxic properties produced by the pathogenic bacterium X. albilineans [42]. As a self-resistance factor, AlbG protects X. albilineans from the antibiotic and cytotoxic effects of albicidin produced by X. albilineans itself. Albicidin shares a common mode of action with fluoroquinolines, also stabilizing the DNA gyrase-cleaved DNA complex and leading to single and double-strand breaks and eventual cell death [42]. X. albilineans uses multiple self-protection mechanisms, including the DNA mimicry of the AlbG PRP. AlbG increases resistance of the E. coli gyrase to albicidin both in vivo and in vitro, and at higher concentrations it inhibits supercoiling by the E. coli gyrase even in the absence of albicidin [42].
The three-dimensional structure of AlbG was solved by Vetting et al. in 2011 [19]. The structure is similar to other Qnr proteins, having eight complete coils composed of a mixture of type II and type IV with one half coil as the zeroth coil and a quarter coil as ninth coil, capped at the N-terminus of the Rfr helix by a small N-terminal extension (residues 1–8) and capped at the C terminal end of the Rfr helix by an 11-residue α helix that is involved in the formation of the head-to-head functional dimer (Figure 8, top panel). A 13-residue loop insertion (T87-A99) disrupted the β helix structure of AlbG, with the loop and β-helical kink stabilized by several noncanonical PRP residues [19]. The dimer interface established by the head-to-head interaction of the C-terminal helix of two AlbG molecules involves 36 amino acids (chain A: 18 residues and chain B: 18 residues) that involved the formation of a hydrophobic core involving eight aromatic and aliphatic sidechains from each chain and interactions between five charged sidechains from each chain (Figure 8, bottom panel). The surface area for the dimer interface was 911 Å2 and the binding energy for dimer formation was −13.5 kcal/mol.
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Figure 8. Structure and analysis of AlbG. The top panel shows the ribbon diagrams of the structure for four different orientations (at left) and the corresponding electronic potential surface plots (at right). The bottom panel is the interface model calculated by Intersurf and depicted using Chimera.

2.3.6. PENT (6FLS)

In 2018, Notari et al. reported the three-dimensional structure of PENT [43], a PRP from the human pathogen Clostridium botulinum, which is a homolog of the fluoroquinoline resistance protein, MfpA from M. Typhimurium (20.2% sequence identity and 39.3% sequence similarity over 183 residues). PENT is made up of 217 residues, crystallizes as a dimer and adopts a right-handed quadrilateral β helix with eight coils composed of a mixture of type II and type IV β turns, with a 12-residue α helix with its axis perpendicular to the β helix axis capping both the N- and C-termini of the β helix (Figure 9). The head-to-head dimer interface is mediated by the C-terminal α helix cap of each of two PENT molecules (Figure 9, top panel). The head-to-head dimer interface interaction was observed between chains A and B and between chains C and D in the crystallographic asymmetric unit. The architecture of the dimer interface involved the formation of a short parallel β involving A197-I199 on chain A and I213-V215 on chain B, orthogonally oriented α helices (S200-G212 on each chain), and another short parallel β sheet formed by residues I213-V215 on chain A and residues A197-I199 on chain B (Figure 9, bottom). The dimer interaction involved 37 residues (chain A: 18, chain B: 19) and 63 non-bonded contacts mediated by a network of aromatic and aliphatic sidechains that formed a hydrophobic core with I199, M201, I213, and I214 all making six or more contacts in chain A and with S189, I199, W211, I213, and I214 making at least six contacts in chain B (Figure 9, bottom panel). The interface area of those two interactions was the same at ~1035 Å2 and the energy of the interaction was −20 kcal/mol. Although the PENT PRP forms a head-to-head dimer with an overall structure similar to that of known PRP gyrase inhibitors, i.e., the MfpA and EfsQnr, it lacked the conserved extra-helix loops observed in other PRP gyrase inhibitors, such as QnrB1, AhQnr, and AlbG. At this time, the function of PENT has not been confirmed experimentally.
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Figure 9. Structure and analysis of PENT. The top panel shows the ribbon diagrams of the structure for four different orientations (at left) and the corresponding electronic potential surface plots (at right). The bottom panel is the interface model calculated by Intersurf and depicted using Chimera.

2.4. Ubiquitin E3 Ligases

2.4.1. SopA (2QYU, 2QZA, 3SY2 and 5JW7)

Salmonella enterica serovar typhimurium, a rod-shaped, flagellate, facultative anaerobic, Gram-negative pathogenic bacterium, stimulates inflammatory responses in the intestinal tract that are required in order for it to replicate in the intestinal tract [44]. Bacterial pathogens can infect host cells and stimulate the inflammatory response by delivering effector proteins by either a type III or type IV secretion system [45]. S. Typhimurium uses a type III secretion system to deliver effector proteins to its host cells [46]. One of the effector proteins is SopA, which is a Homologous to E6AP C-terminus (HECT)-type E3 ligase [47] that is required for efficient stimulation of inflammation in S. Typhimurium infections [48]. The process of attaching ubiquitin to a targeted protein requires an enzyme cascade including ubiquitin activation enzyme (E1), conjugating enzymes (E2), and ligase (E3). HECT E3s are of two types, with one E3 functioning by forming a thioester intermediate with ubiquitin to transfer ubiquitin to substrate and the other is called a really interesting new gene (RING) E3. Bacterial infection is normally sensed by host pattern recognition receptor-mediated detection of pathogen-associated molecular patterns (PAMPS), which induces a pro-inflammatory response to fight the infection [49]. The tripartite motif-containing (TRIM) TRIM56 and TRIM65 host RING [50] E3 ubiquitin ligases are normally involved recognizing foreign proteins and stimulating release of interferons to communicate to nearby cells to launch an immune response to combat infection [49]. Kamanova et al. showed that SopA inhibits the host immune responses by targeting the TRIM56 and TRIM65 host RING [50] E3 ubiquitin ligases [51].
In 2008, Diao et al. solved the structure of SopA163–782, a fragment of the full-length SopA that was stable to proteolysis [44]. The structure was described as being organized into a 147-residue N-terminal β-helix domain (residues 163–370), a central domain (residues 371–590), a helical linker (residues 591–611) and a C-terminal domain (residues 612–782). SopA was the first PRP-containing multi-domain protein to have its structure determined. The SopA structure contains an N terminal PRP domain (around 200 amino acids) and a catalytic domain containing N- and C-lobes (Figure 10, top panel). The Rfr domain in SopA is comprised of four complete coils composed of a mixture of type II and IV β turns. In face 2 of the first coil, the β helix is replaced by two α-helixes. One is composed of five residues from T206 to I210 and the other is made up of six residues including P212 to E217. After the last complete Rfr coil, there is an extended quarter coil connected with the linker of β-helix domain and central domain. In 2017, Fiskin et al., solved another structure of SopA bound to the RING domain of TRIM56 [49] which revealed the structural basis for selectivity of SopA for TRIM56 and TRIM6 showing that the TRIM56 domain interacts with the interface of the β-helix and the N-lobe domains of SopA through packing with the first Zn2+-binding loop in a cleft of SopA. Using a combination mutation experiments, it was shown that this interaction relied on three key residues including T338 of SopA, and L25 and E26 of TRIM56. In TRIM56, E25 interacts with R296, H297, and K298 via polar contacts while L25 is inserted between the hydrophobic pocket constructed by P334 and F345. In SopA, T338 has a close hydrophobic contact with central α-helix of TRIM56. From the mutation experiments, T338 was also shown to support the interaction between SopA and TRIM65 (Figure 10, bottom panel) [49]. The authors performed structure-based biochemical analyses to show that SopA inhibited the TRIM56 E3 ligase activity by occluding the E2-interacting surface of TRIM56, and further showed that SopA ubiquinates TRIM56 and TRIM65 resulting in their proteasomal degradation during infection, thus disrupting the host immune response to S. typhimurium infection.
Biomolecules 11 00638 g010 550
Figure 10. Structure and analysis of SopA. The top panel shows ribbon diagrams of the structure (PDB ID: 2QZA) for four different orientations (at left) and the corresponding electronic potential surface plots (at right). The bottom panel (left figure) shows the overall interaction between SopA and Trim56 (5JW7) and the right figure shows the details of the interaction. SopA is colored orange and Trim56 is colored cyan.

2.4.2. NleL (3NB2, 3NAW, and 3SQV)

The non-Lee-encoded effector ligase (NleL) from enterohemorrhagic Escherichia coli (EHEC) 0157:H7 is a homolog of SopA from S. Typhimurium. Lin et al. [52] solved the crystal structure of NleL and showed that NleL functionally and structural mimics eukaryotic E3 ligases and catalyzes formation of unanchored polyubiquitin chains using linkages with residues Lys6 and Lys 48 and with the catalytic cysteine residue forming a thioester intermediate with ubiquitin [52]. In recent studies, it has been shown that NleL uses JNK proteins (stress-activated protein kinase) as the first substrate to promote EHEC-induced attaching and effacing (A/E) lesions [53] and interacts with TRAF2, TRAF5, TRAF6, IKKα, and IKKβ to disrupt the host NF-κB pathway [54].
The structure of NleL shares a common N-terminal PRP domain with SopA [52][55], which contains five and a half Rfr coils mostly composed of type II β turns with one type IV β turn from L213 to L216, one α helix at the N terminus and three α helices at the C terminus flanking the β helix domain. Superposition of the SopA and NleL crystal structures indicated that the PR and N-lobe domains maintain a fixed relative orientation, the C-lobes can adopt different orientations relative to the PR and N-lobe, perhaps but due to their different functional requirements [52]. Based on the structures of complex between NleL and the UbcH7 domain (3SQV) [55], UbcH7 contacts the N-lobes by both hydrogen bond and van der Waals interactions. In SopA, the PRP domain is N-terminal to the catalytic domain and the carbohydrate-modified substrate proteins may be recognized by that. However, the actual functions and substrates still remain unknown. Although the function of PR domains is still unknown, a cleft at the interface of PRP domain and N-lobe domain provide some clues to identify the potential functions. Two of tripartite-motif-containing (TRIM) E3 ligases, belonging to the family of RING-type E3 ligases, are involved in the regulation of SopA [51]. Complex structure involving SopA and TRIM 56 unmasked that the first Zn2+-binding loop of TRIM 56 contacts with the cleft of SopA. In TRIM 56, Leu25 and Glu 26 are the two key amino acids contacting SopA even though they adopt different strategies. Leu25 interacts with Phe345 and Pro334 of SopA by inserting into a hydrophobic pocket while Glu26 contacts Arg296, His297, and Lys298 by their polar groups. (Figure 11). There are two complexes in the crystallographic asymmetric unit. In the interaction between chain A (NleL) and chain C (E2 UbcH7), one salt bridge, two hydrogen bond and 47 non-bonded contacts form the contact interface involving 15 residues from chain A and 13 residues from chain C. Asn578 from NleL and Phe63 from E2 UbcH7 are responsible for most of the contacts for this interaction. The interface area between two chains was 1640 Å2 with the energy of interaction at −11.5 kcal/mol. Different from interaction between chain A and C, in the interaction between chain B and chain D, a disulfide bond between Cys753 (chain B) and Cys86 (chain D) stabilized the interaction. Twenty residues from chain B and 15 residues from chain D formed the interaction and the interface area was 1922 Å2 with an energy of formation of −15.3 kcal/mol. Phe63 from chain D was major contributor to support this interaction.
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Figure 11. Structure and analysis of NleL. Ribbon diagrams of the structure (PDB ID: 3NAW) for four different orientations (at left) and the corresponding electronic potential surface plots (at right).

2.5. Synaptic Vesicle Glycoprotein 2 Receptors

SV2C-LD (4JRA, 5JMC, 5JLV, 5MOY, and 6ES1)

Synaptic vesicles, also referred to as neurotransmitter vesicles, store various neurotransmitters that are released at the synapse, i.e., the junction, or between nerve cells. The synaptic vesicles are essential for propagation of nerve impulses and constantly regenerated in nerve cells. The synaptic lumen refers to the volume contained inside the synaptic vesicles. Synaptic vesicle glycoprotein 2 (SV2) receptors represent a protein family with two essential complementary major isoforms, SV2A and SV2B, and one minor isoform, SV2C, that are putative transport proteins [56]. All three isoforms are composed of a 12-transmembrane domain and a luminal domain (SVC-LD), i.e., the domain sticks into the vesicle lumen, composed of a four and half-coil PRP β helix that acts as a receptor for binding to Botulinum neurotoxin A (BoNT/A) from the bacterium C. botulinum and related bacteria [57]. Botulinum neurotoxins (BoNTs) are the most toxic class of bioweapons and also have a popular and widely used cosmetic application as an anti-wrinkle agent, e.g., Botox [58]. BoNTs exist as seven main serotypes from BoNT/A to BoNT/G [58]. In 2006, Dong et al. showed that the luminal domain of SV2 (SVC-LD) acts as a receptor for BoNT [57]. The SV2C-LD is necessary in the process of translocation of BoNT/A and glycosylation of SV2C-LD and SV2 glycan are also crucial for BoNT/A binding to neurons [58].
From 2014 to 2018, five structures were reported for complexes between BoNTs and the SV2C-LD (also referred to as SV2C-L4) [58][59][60][61]. The LD of SVC2 is a five-coil PRP domain composed exclusively of type IV β turns (Figure 12). All five structures were similar with slight variations in the relative orientations between the SV2C-LD and the different subtypes of BoNT/A. The interaction between the BoNT/A and the SV2C-LD receptor occurs at the exposed β-strand of the 5th Rfr coil at C-terminal un-capped edge of the PRP domain by forming an interchain β-sheet mediated by backbone-to-backbone hydrogen bonds between the open β strand of SV2C-LD and the β-strand edge of the BoNT/A. Even though the structural features of the multiple SV2C-LD/BoNT/A complexes are similar, the orientation of the BoNT/A relative to the SV2C-LD β-helix receptor varied slightly among the structures due to differences in amino acids sidechains mediating the binding interaction and due to flexibility of the interactions [61]. For example, in two structures reported for the same complex SV2C-LD/BoNT/A but crystallized in different space groups and with different resolution (PDB-IDs 5MOY and 6ES1), the orientation of the SV2C-LD β-helix was rotated by 15° relative to BoNT/A to maintain the tight interaction between β-hairpin of BoNT/A and the continuing β-sheet [61]. This rotation caused shifts in both components. The residues in the β-hairpin (T1146 and N1147) moved by 1.8 Å and the residues from C-terminus of SV2C-LD (N480 to Y497, D546 to K566) moved between 0.4 and 8.1 Å [61].
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Figure 12. Structure and analysis of SV2C. The top panel is the ribbon diagram of the structure and electronic potential surface analysis. The bottom panel is the interface model calculated by Chimera.

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