15 nots - 1 Lecture 15 November 3, 2008 Matrix Remodeling...

Info iconThis preview shows pages 1–3. Sign up to view the full content.

View Full Document Right Arrow Icon
1 Lecture 15 November 3, 2008 Matrix Remodeling Metalloproteinases and cancer cell invasion Some test is taken verbatim from the literature cited MMP classification (Nagase et al (2006) Structure and function of matrix metalloproteinases and TIMPs Cardiovascular Research 69: 562-573) Based on domain organization and substrate preference, matrix metalloproteinases (MMPs) are grouped into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs and others. The focus the lecture is on collagenases and gelatinases. Degraded collagen is referred as gelatin. Collagenases cleave intact collagen molecules, whereas gelatinases cleavage degraded collagens. Collagenases (MMP-1 and MT1-MMP) cleave interstitial collagens I, II and III into characteristic ¾ and ¼ fragments (a single cleavage site in the C-terminus), but can also digest other ECM molecules and soluble proteins. Once cleaved, the digested collagen is referred to as gelatin, which is the target of gelatinases. Gelatinases (MMP-2 and MMP-9) readily digest gelatin with the help of three fibronectin type II repeats that bind to gelatin/collagen. They also digest a number of ECM molecules including type IV, V and XI collagens, laminins, aggrecan core protein. MT-MMPs in mammals include four type I transmembrane proteins and two glycosylphosphatidylinositol-anchored proteins. The focus will be on MT1-MMP. MMP activation In inactive proMMPs, the SH group of a cysteine residue in the prodomain interacts with the catalytic zinc ion in the catalytic domain. Activation requires the removal of the prodomain, freeing the catalytic zinc atom. Moreover, for some MMPs (e.g. proMMP-1), the prodomain interacts with the Hemopexin domain, rendering it in a “closed” configuration in contrast to the “open” configuration of the active MMPs. This change in configuration is considered to create the collagen binding site. Tissue Inhibitors of Metalloproteinases-TIMPs (Rapi et al (2006) JBC 281: 23386) The activity of various MMPs are controlled at the protein level via inhibition and activation by the following four homologous tissue inhibitors of metalloproteinases (TIMPs): TIMP-1, -2, -3, and -4. TIMPs inhibit the MMPs in a 1:1 stoichiometry by tightly binding to the active site of the enzyme primarily through their N-terminal domains. All four TIMPs inhibit active forms of most of the MMPs, but some differences in their inhibitory properties have been reported. For example, TIMP-2, TIMP-3 and TIMP-4 are effective inhibitors of MT-MMPs, whereas TIMP-1 is a very poor inhibitor of these enzymes. TIMP-1 is an effective inhibitor of soluble MMPs. Vu and Werb (2000) Matrix metalloproteinases: effectors of development and normal physiology. Genes & Development 14:2123-2133 Abstract The MMP family of extracellular proteinases regulated development and physiologic events. Genetic analyses using transgenic mice that have gain and loss of function of
Background image of page 1

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
2 MMPs or their endogenous inhibitors, the TIMPs, and pharmocogenetic studies with
Background image of page 2
Image of page 3
This is the end of the preview. Sign up to access the rest of the document.

This note was uploaded on 09/29/2009 for the course CSB csb327 taught by Professor Ringuitte during the Fall '08 term at University of Toronto.

Page1 / 5

15 nots - 1 Lecture 15 November 3, 2008 Matrix Remodeling...

This preview shows document pages 1 - 3. Sign up to view the full document.

View Full Document Right Arrow Icon
Ask a homework question - tutors are online