CSB327 Lecture 11 Summary

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Cell and Systems Biology
Maurice Ringuette

Lecture 11 Cell-matrix adhesion complexes - Highly dynamic structures subject to assembly and disassembly - Low similarity in the composition of FAs from one cell type to another - Focal complexes (FCs) o Relatively small, transient sites of adhesions - Focal adhesions (FAs) o Large, stable sites of adhesions o Found in non-motile cells - Fibrillar adhesions (FBs) o Elongated fibrils o Form when FN has directionality Fibronectin - An ECM glycoprotein with specific binding sites for other ECM proteins and for cell surface receptors - A dimer of two similar, but not identical polypeptides joined by a disulfide bridge at C-terminus o Each domain is encoded by a separate exon o FN gene evolved by multiple exon duplication - Four domains o Self-association domain at N-terminus  FN matrix polymerization o Collagen binding domain  Collagen fibrillogenesis requires FN fibrillogenesis  Collagen can self-assemble  FN is a cell-mediated event o Cell binding domain  There are 2 FN type III (FN-III) modules  RGD sequence (type III module #10) o The site of cell binding via α5β1 and αVβ3 integrins  Synergy sequence (type III module #9) o A role in modulating FN’s association with α5β1 integrins o Without the synergy sequence, it decreases the presentation of the RGD sequence to integrins o Heparin binding domain o Disulfide bridge at C-terminus - Three types of modules o FN type I modules (FN-I)  Disulfide bridged o FN type II modules (FN-II)  Disulfide bridged o FN type III modules (FN-III)  Not disulfide bridged  More flexible  Most commonly found protein in vertebrates  Ig-like folds  Composed of seven β-strands arranged in two anti-parallel β-sheets connected by flexible loops  Create new binding sites for ligands through small changes in the loops  Can be easily integrated into proteins - Two forms o Plasma form secreted by hepatocytes (soluble, non-fibrillar)  IIIB/EDA and IIIA/EDA modules removed by alternative splicing  Enhances clotting, wound repair, and phagocytosis  The plasma does not express integrins in activated form until needed o Cellular form secreted by fibroblasts (insoluble, fibrillar)  IIIB/EDA and IIIA/EDA is only found in cFN  Absence of one domain by alternative splicing has no effect on normal development  Absence of both domains is embryonically lethal  Deposited in the ECM  The cell expresses integrins in the activated form to allow FN fibril assembly  Cross-linked by additional disulfide bonds o The V region is essential for FN dimer secretion - FN fibril assembly o FN polymerization requires N-terminal repeats and C-terminal disulfide bridge o Compact soluble FN binds to integrin via its cell binding domain  Initiates integrin clustering  Stimulates open conformation of integrin  Induces reorganization of actin cytoskeleton  Activates intracellular signalling complexes o Cell contractility extends FN conformation  Exposes cryptic binding domains  Allows FN-FN interactions to form FN fibrils  Initially forms short fibrils around the cell periphery o Detergent-soluble fibrils  Eventually forms longer and thicker fibrils creating a dense matrix o Detergent-insoluble fibrils  FN fibrils converted from soluble to insoluble is irreversible  Due to covalent cross-linking by transglutaminase  Due to partial unfolding of β-strands leading to β-strand exchange  FN fibrils aligned in parallel to actin cytoskeleton Integrin is a transmembrane receptor that links ECM to actin cytoskeleton - No kinase activity o Requires FAK - A αβ heterodimer o The ectodomain β strand binds to the RGD sequence on FN-III 10 o The ectodomain α strand mediates the interaction Relationship between focal adhesions and cell motility - Lacking FA o Unable t
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