CSB327 Lecture 13 Summary

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Cell and Systems Biology
Maurice Ringuette

Lecture13 Matrix metalloproteinases (MMPs) - Structure of soluble MMPs o Pre-peptide domain (e.g., signal peptide) o Pro-peptide domain  Cysteine switch o Catalytic domain  FN type II repeats  Essential for gelatinases to cleave elastin, gelatin, and type IV collagen  Gives substrate specificity  Zinc ion (Zn++) o Hemopexin domain  Essential for collagenases to cleave collagen  Gives substrate specificity - Activation of MMPs o Inactive conformation (e.g., pro-MMPs)  SH group of a cysteine residue in the pro-peptide domain interacts with catalytic zinc ion in the catalytic domain  Cys-Zn++ interaction o Activation requires the removal of the pro-peptide domain to free the catalytic zinc ion  Triggers the cysteine switch mechanism - Inhibition of MMPs o TIMPs are the major endogenous regulators of MMP and ADAMs activities in tissues o TIMPs inhibit MMPs in a 1:1 stoichiometry by binding to the catalytic domain  TIMP-1 is an effective inhibitor of soluble MMPs only, but a poor inhibitor of MT-MMPs  TIMP-2, TIMP-3, TIMP-4 are effective inhibitors of MT-MMPs  TIMP-2 inhibits soluble MMPs and MT-MMPs, but better inhibitor against MT-MMPs - Function of MMPs o Remodeling of ECM (e.g., dermal wound healing) o MMPs and TIMPs are important for cell migration, invasion, proliferation and apoptosis o During wound closure, the formation of a provisional matrix consisting of fibrin and plasma proteins (e.g., clots) o During wound repair, keratinocytes migrate to remove the provisional matrix and re-epithelialize the wound  Dependent on MMP-1 to degrade the ECM  Dependent on activation of fibroblasts into contractile myofibroblasts to contract the ECM - Classification of MMPs o Collagenases cleave intact collagen (e.g., MMP-1 and MT1-MMP)  Cleave interstitial collagens I, II and III into ¾ and ¼ fragments  Cleave at a single site in the C-terminus  Can also digest other ECM molecules o Gelatinases cleave degraded collagen (MMP-2 and MMP-9) o Sheddases (MT1-MMP)  Structure of MT-MMPs  Pre-peptide domain  Pro-peptide domain (Ca2+) o Furin recognition (cleavage) site  Catalytic domain (Zn2+)  Hemopexin domain  Two ways of anchoring into the membrane  Transmembrane domain (and cytoplasmic domain)  GPI anchor  Activation of MT-MMPs  Inactive conformation is a folded structure involving ionic bond between cysteine residue and zinc ion o Like soluble MMP inactivate conformation  Activation requires the removal of the pro-peptide domain at furin cleavage site o Pro-peptide domain is cleaved in the trans-Golgi network
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