Zinc Transporters in Different Biological Kingdoms: Comparison
Please note this is a comparison between Version 2 by Fanny Huang and Version 1 by Kenji Inaba.

Zinc transporters take up/release zinc ions (Zn2+) across biological membranes and maintain intracellular and intra-organellar Zn2+ homeostasis. Since this process requires a series of conformational changes in the transporters, detailed information about the structures of different reaction intermediates is required for a comprehensive understanding of their Zn2+ transport mechanisms. Various Zn2+ transport systems have been identified in bacteria, yeasts, plants, and humans. 

  • zinc transporter
  • ZnT
  • cryo-EM

1. Introduction

Zinc ions (Zn2+), an essential trace element in bacteria, fungi, plants, and animals, including humans [1], serve as a key component in many signal transduction processes and act as an essential cofactor for many proteins and enzymes [2,3][2][3]. Zinc deficiency causes several human diseases [4,5,6,7,8,9,10,11,12,13][4][5][6][7][8][9][10][11][12][13]; indeed, zinc supplements have beneficial effects on human health [8,14,15,16,17,18,19][8][14][15][16][17][18][19]. However, excessive adsorption of Zn2+ leads to disruption of the gastrointestinal flora balance, deficiency of other essential heavy metals, including iron, copper, and manganese, and reduction in immune function [20,21,22,23][20][21][22][23]. Zn2+ also plays an important role in the physiology of organisms such as plants and bacteria [24,25][24][25]. In plants, zinc deficiency is linked to growth defects and inhibition of flowering [26,27][26][27]. Additionally, Zn2+ is responsible for the virulence of some bacteria [28]. Since Zn2+ is involved in numerous biological events, humans, plants, yeasts, and bacteria have evolved elaborate Zn2+ transport systems that respond to Zn2+ perturbation.
Failure of the Zn2+ transport systems plays a role in diseases such as cancer [29[29][30],30], Alzheimer’s [31[31][32],32], and Parkinson’s [33[33][34],34], as well as temporary zinc deficiency in newborns [35], perinatal fatal cardiomyopathy [36], risk of febrile seizures [37], Lowe’s syndrome [38], disorders of muscle tone with polycythemia [39[39][40],40], and chronic liver disease [40]. Therefore, human zinc transporters (ZnTs) are potential targets of drugs and preclinical diagnostic tests. Owing to the important physiological roles, and pharmacological and preclinical diagnostic significance of Zn2+ transport systems, a variety of biochemical, structural, physiological, and genetic experiments have been carried out over the past several decades to better understand their functions and mechanisms. The most comprehensively studied bacterial zinc transporter is YiiP, which works in Escherichia coli and Shewanella oneidensis (EcYiiP and SoYiiP, respectively) [41,42,43,44,45,46,47,48,49][41][42][43][44][45][46][47][48][49]. These transporters are a convenient model to study the general mechanisms underlying Zn2+ transport. The most intensively studied mammalian ZnTs are SLC30A7/ZnT7 [50] and SLC30A8/ZnT8 [51,52][51][52]. OuResearchers' interests in ZnT family members stem mainly from their roles in maintaining Zn2+ homeostasis in cellular organelles throughout the body and the fact that their dysfunction causes serious diseases.
As is the case for other membrane transporters, ZnTs undergo conformational conversion to transport Zn2+ across biological membranes. To fully understand the mechanism underlying Zn2+ transport, high-resolution structures of the transporters have been captured in different states. The first X-ray crystal structure of a zinc transporter (Table 1) was reported for EcYiiP [41[41][42],42], followed by the EM structure of SoYiiP [43,44,45,46][43][44][45][46]. More recently, cryo-EM structures of vertebrate ZnTs have been reported (Table 1); these include Homo sapiens ZnT7 (HsZnT7) [50], Homo sapiens ZnT8 (HsZnT8) [51], and Xenopus tropicalis ZnT8 (XtZnT8) [52]. These structures allow us to propose an updated model of ZnTs-mediated Zn2+ transport. Of note, ouresearchers' recent structural and biochemical studies on HsZnT7 revealed the role of its cytosolic histidine-rich loop (His-loop) in efficient Zn2+ uptake [50]. Thus, researchers have built on the structural and mechanistic foundations of ZnTs in the biological kingdom, while making significant progress regarding research into other members with Zn2+ transport functions.
Table 1.
X-ray and cryo-EM structure of zinc transporters (ZnTs).
Proteins Main Functions Organisms States Conformations (PDB Code) Ligands Methods References
YiiP Transport Zn2+ out of the cytoplasm and into the periplasm Escherichia coli Homodimer Outward-facing (2QFI, 3H90) Zn2+ X-ray diffraction [41,42][41][42]
Shewanella oneidensis Homodimer Inward-facing (3J1Z, 5VRF, 7KZZ (1)) Zn2+ Electron microscopy [44,45,46][44][45][46]
  Homodimer Inward-facing occluded (7KZX) Zn2+ [43]
ZnT7 Transport Zn2+ out of the cytoplasm and into the Golgi lumen Homo sapiens Homodimer Outward-facing (8J7T) Apo Electron microscopy [50]
Homodimer Outward-facing (8J7U) Zn2+
Heterodimer Inward-facing and outward-facing (8J7V (2)) Apo
Heterodimer Inward-facing with Zn2+ and outward-facing (8J80 (3)) Zn2+, Apo
Heterodimer Inward-facing with Zn2+ and outward-facing with Zn2+ (8J7W) (4) Zn2+
ZnT8 Transport Zn2+ out of the cytoplasm and into the insulin secretory granule H. sapiens Homodimer Outward-facing (6XPE) Zn2+ Electron microscopy [51]
Heterodimer Outward-facing and inward-facing (6XPF) Apo
Xenopus tropicalis Homodimer Outward-facing (7Y5G) Zn2+ [52]
Homodimer Outward-facing (7Y5H (5)) Apo
(1) This structure was observed in the presence of 0.5 mM EDTA. (2) This structure was observed in the absence of Zn2+. (3) This structure was observed in the presence of 10 μM Zn2+. (4) This structure was observed with addition of 200 and 300 μM Zn2+. (5) This structure was observed at low pH.

2. Zn2+ Transport Systems in Prokaryotes and Eukaryotes

Prokaryotes and eukaryotes have developed a variety of Zn2+ transport systems to promote the uptake or efflux of Zn2+ across biological membranes. ZnTs can be divided into three major groups depending on the mode of transport: Uniporters that transport Zn2+ alone; symporters that transport Zn2+ in the same direction as other ions, such as protons; and antiporters that transport Zn2+ and another ion in opposite directions, such that the binding of one is concomitant with the release of the other. In general, uniporters require no external energy input and transport specific molecules along their concentration gradients; they are therefore passive transporters. However, it can also act as an active transporter if the transport process is against the concentration gradient. By contrast, symporters and antiporters use the energy stored in the concentration gradient of another ion, in many cases, a proton, to transport specific molecules against their concentration gradients. In this regard, symporters and antiporters can be regarded as active transporters. In addition, some P-ATPases and ABC transporters transport Zn2+ using ATP as an external energy source to overcome the Zn2+ concentration gradient.
Zinc transporters (ZnTs) and ZRT- and IRT-related proteins (ZIPs) are the two major Zn2+ transport families found universally in bacteria, yeasts, plants, and animals, including humans. ZnTs and ZIPs selectively transport Zn2+, but in opposite directions: ZnTs export Zn2+ from the cytoplasm, whereas ZIPs import Zn2+ into the cytoplasm. Thus, ZnTs and ZIPs play important roles in maintaining homeostasis of intracellular and intra-organelle Zn2+ levels.
While ZntB from Escherichia coli (EcZntB) acts as a Zn2+/H+ symporter [53], many ZnTs function as proton-driven antiporters, exchanging H+ in the extracellular space or organelle lumens for Zn2+ in the cytoplasm [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. By contrast, there is no clear evidence that ZIPs use proton energy flux to transport Zn2+ across the membranes. However, recent biochemical studies suggest that, like ZnTs, Bordetella bronchiseptica ZIP (BbZIP) may function as a Zn2+/H+ antiporter [56].

3. ZnTs

ZnTs belong to the cation diffusion facilitator (CDF) family, which can be classified into three groups: Zn-CDFs, Zn/Fe-CDFs, and Mn-CDFs [57,58][57][58]. Zn-CDFs consist of Zn2+ and Co2+ transporters, including ZitB-like, ZnT1-like, and Zrc1-like proteins. The ZitB-like clusters are from E. coli. The ZnT1-like clusters include only metazoans. The Zrc1-like cluster includes only fungal CDFs originating from Ascomycetes, Basidiomycetes, and Zygomycetes. Zn/Fe-CDFs are cation-efflux pumps that transport Fe2+ or Zn2+, and also Co2+, Cd2+, and Ni2+. Mn-CDFs include metal tolerance proteins (MTPs) from plants.

3.1. Mammalian ZnTs

Ten ZnTs (ZnTs 1–10) have been identified in mammals, including humans [59,60][59][60]. All ZnTs are Zn-CDF members, although ZnT10 is more likely a manganese transporter [59,60,61][59][60][61]. Based on their amino acid sequence similarities, ZnTs are divided into four subgroups: Group 1 includes ZnT5 and ZnT7; group 2 includes ZnT2-ZnT4 and ZnT8; group 3 includes ZnT1 and ZnT10; and group 4 includes ZnT6 and ZnT9 [60]. Most ZnTs form a homodimer composed of the same protomers [50[50][51][52],51,52], whereas ZnT5 and ZnT6 form a heterodimer including two different protomers [62], and all are located on the plasma or organelle membranes, where they control intracellular and extracellular Zn2+ balance [59,63][59][63]. Specifically, ZnT7 transports Zn2+ into the lumen of the pre-cis- and cis-Golgi, whereas ZnT5/6 and ZnT4 transport Zn2+ into the lumen of the medial- and trans-Golgi [64]. ZnT7 and ZnT5/6 are responsible for the Golgi-to-ER retrograde transport of the ER chaperone ERp44 [64]. This system is involved in the maturation and activation of some secretory proteins during transport through the early secretory pathway [65].

3.2. Plant ZnTs

Metal tolerance proteins (MTPs) are bivalent cationic transporters in plants that play crucial roles in metal tolerance and homeostasis in metal non-hyperaccumulators (e.g., Arabidopsis thaliana) and hyperaccumulators (e.g., Arabidopsis halleri and Noccaea caerulescens) [66]. MTPs are classified into seven groups based on their amino acid sequence similarities [67]. Thus, plant MTPs are very diverse so as to satisfy the need to absorb or detoxify specific metals. A. thalaina has 12 MTPs, while P. trichocarpa MTP has up to 22 MTP genes [68]. In A. thaliana, AtMTP1 and AtMTP3 ZnTs localized on the vacuole membrane maintain Zn2+ homeostasis [69,70,71][69][70][71]. AtMTP1 and AtMTP3 are involved in the sequestration of excess cytoplasmic Zn2+ into vacuoles [71]. Whereas AtMTP1 is more ubiquitously expressed, expression of AtMTP3 is restricted to the root epidermis and cortex [69,72][69][72]. Like mammalian ZnT5 and ZnT6, AtMTP5 and AtMTP12 form a heterodimer at the Golgi membrane and transport Zn2+ into the Golgi lumen [73].

3.3. Yeast ZnTs

OuResearcher s'understanding of ZnTs in yeast derives primarily from Saccharomyces cerevisiae. In S. cerevisiae, vacuolar ZnTs ZRC1 and COT1 act as Zn2+/H+ antiporters and regulate Zn2+ homeostasis by transporting and storing Zn2+ in the vacuole [74,75][74][75]. ScZRC1 senses Zn2+ availability in the cytosol, possibly through the histidine-repeat motifs, and transports Zn2+ from the cytosol to the vacuole when cytosolic Zn2+ is abundant, thereby conferring resistance to Zn2+ toxicity [76,77][76][77]. S. cerevisiae also possesses Msc2 and Zrg17, which transport Zn2+ from the nucleus and ER to the cytoplasm [78]. ScMsc2 and ScZrg17 interact physically to form a heterodimer and likely serve to maintain the Zn2+ levels in the ER of Zn2+-adequate cells [79,80,81][79][80][81]. Schizosaccharomyces pombe also has a zinc transporter, called ZHF1, which maintains Zn2+ homeostasis in the ER and nucleus and sequesters Cd2+ into the ER [82]. The structures of yeast ZnTs have not yet been reported. While ScZRC1, ScCOT1, and ScZrg17 are predicted to have six transmembrane (TM) helices, ScMsc2 is presumed to contain up to 16 TM helices.

3.4. Bacterial ZnTs

Bacterial ZnTs YiiP, ZitB, and CzcD have been functionally characterized. Insight into the structural features and Zn2+ transport mechanisms of bacterial ZnTs comes primarily from YiiP. YiiP was first identified in Escherichia coli [83]. In vitro, YiiP also binds Hg2+, Co2+, Ni2+, Mn2+, Ca2+, and Mg2+ but is unlikely to transport them efficiently [84]. Like mammalian ZnTs, YiiP functions as a Zn2+/H+ antiporter [43,48][43][48]. Other ZnTs have been identified recently in bacteria. ZitB conducts Zn2+ efflux across the cytoplasmic membrane, thereby reducing Zn2+ accumulation in the cytoplasm and rendering bacteria more resistant to Zn2+ [85]. By contrast, ZntA, a Zn2+-transporting P-ATPase, is required for growth at more toxic concentrations [85]. CzcD is a Cd2+, Co2+, and Zn2+/H+-K+ antiporter involved in maintaining intracellular divalent cation and potassium homeostasis through active efflux of Zn2+, Cd2+, and Co2+ in exchange for K+ and protons [86].


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