The Diverse Roles of TIMP-3
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  • Release Date: 06 Jan 2021
  • TIMP-3
  • ECM
  • AMD
  • sorsby
  • retina
  • Alzheimer’s disease
  • dementia
Video Introduction

This video is adapted from 10.3390/cells9010039

Tissue inhibitors of metalloproteinases (TIMPs) are proteins expressed ubiquitously in the body which play important roles through their ability to reversibly inhibit enzymes belonging to the zinc protease superfamily, predominantly matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) [1]. The TIMP family consists of four members: TIMP-1, -2, -3 and -4. Whilst TIMPs are widely regarded as broad-range MMP inhibitors, each protein exhibits differences in their specificity. TIMP-3, the focus of this review, is found in chromosome 22q12.3 and is nested within an intron of the gene synapsin 3 (SYN3); a feature shared with TIMP-1 and TIMP-4 which are located within introns of synapsin 1 (SYN1) and synapsin 2 (SYN2), respectively [1]. TIMP-2 however, is not associated with any of the synapsin genes. The relationship between synapsin and TIMPs appears to be evolutionarily conserved, having been identified in the fruit fly (Drosophila melanogaster) and the tiger blowfish (Fugu rubripes) [2], although its nature is yet to be elucidated. There is also considerable conservation in the amino acid structure of TIMP family members. Each protein contains an N-terminal domain of approximately 125 amino acids and a C-terminal domain of 64 amino acids, with each domain stabilised by three disulphide bonds that form between conserved cysteine residues [1][3]. TIMP-3 is considered to have a predominantly extracellular role, as the protein is capable of binding to the extracellular matrix (ECM) via its N or C- terminal domains [4][5]. By contrast, TIMP-1, -2 and -4 proteins were considered to predominantly exist in soluble form within the interstitial space of the ECM. However, it has since been shown that these proteins can also interact with cell surface proteins including CD63 and β-1 integrin [6][7][8]. The interaction of TIMP-3 with ECM proteoglycans is primarily mediated via its C-terminal domain. However, binding to the glycosaminoglycan heparin appears to be mediated via the N-terminus [9]. Of the four members of the TIMP family, TIMP-3 possesses the broadest range of inhibition, targeting all members of the MMP family and several of the ADAM and ADAMTs (a disintegrin and metalloproteases with thrombospondin motifs) family members. Independent of its inhibitory capabilities, TIMP-3 is also involved in promoting cell proliferation and regulating angiogenesis and apoptosis [1].

References
  1. Brew, K.; Nagase, H. The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity. Biochim. Biophys. Acta 2010, 1803, 55–71.
  2. Solda, G.; Suyama, M.; Pelucchi, P.; Boi, S.; Guffanti, A.; Rizzi, E.; Bork, P.; Tenchini, M.L.; Ciccarelli, F.D. Non-random retention of protein-coding overlapping genes in Metazoa. BMC Genom. 2008, 9, 174.
  3. Arris, C.E.; Bevitt, D.J.; Mohamed, J.; Li, Z.; Langton, K.P.; Barker, M.D.; Clarke, M.P.; McKie, N. Expression of mutant and wild-type TIMP3 in primary gingival fibroblasts from Sorsby’s fundus dystrophy patients. Biochim. Biophys. Acta (BBA)—Mol. Basis Dis. 2003, 1638, 20–28.
  4. Mohammed, F.F.; Smookler, D.S.; Khokha, R. Metalloproteinases, inflammation and rheumatoid arthritis. Ann. Rheum. Dis. 2003, 62, 43–47.
  5. Langton, K.P.; Barker, M.D.; McKie, N. Localization of the functional domains of human tissue inhibitor of metalloproteinases-3 and the effects of a Sorsby’s fundus dystrophy mutation. J. Biol. Chem. 1998, 273, 16778–16781.
  6. Arpino, V.; Brock, M.; Gill, S.E. The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol. 2015, 44–46, 247–254.
  7. Toricelli, M.; Melo, F.H.; Peres, G.B.; Silva, D.C.; Jasiulionis, M.G. Erratum: Timp1 interacts with beta-1 integrin and CD63 along melanoma genesis and confers anoikis resistance by activating PI3-K signaling pathway independently of Akt phosphorylation. Mol. Cancer 2015, 14, 161.
  8. Jung, K.K.; Liu, X.W.; Chirco, R.; Fridman, R.; Kim, H.R. Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J. 2006, 25, 3934–3942.
  9. Yu, W.H.; Yu, S.; Meng, Q.; Brew, K.; Woessner, J.F., Jr. TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. J. Biol. Chem. 2000, 275, 31226–31232.
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Dewing, J.; Ratnayaka, J.A.; Carare, R.O. The Diverse Roles of TIMP-3. Encyclopedia. Available online: https://encyclopedia.pub/video/video_detail/54 (accessed on 23 February 2024).
Dewing J, Ratnayaka JA, Carare RO. The Diverse Roles of TIMP-3. Encyclopedia. Available at: https://encyclopedia.pub/video/video_detail/54. Accessed February 23, 2024.
Dewing, Jennifer, J. Arjuna Ratnayaka, Roxana O. Carare. "The Diverse Roles of TIMP-3" Encyclopedia, https://encyclopedia.pub/video/video_detail/54 (accessed February 23, 2024).
Dewing, J., Ratnayaka, J.A., & Carare, R.O. (2021, January 06). The Diverse Roles of TIMP-3. In Encyclopedia. https://encyclopedia.pub/video/video_detail/54
Dewing, Jennifer, et al. "The Diverse Roles of TIMP-3." Encyclopedia. Web. 06 January, 2021.