Module 21: Proteins in the ECM PDF

MODULE 21 Proteins in the ECM - Fibrous proteins: Collagen, fibrin, elastin. - Fibrous proteins provide structural/mechanical cues to direct cell behavior. Soluble signals are sequestered by proteoglycans and bind to cell surface receptors to direct cell fate. Integrins (transmembrane receptors) b...

MODULE 21 Proteins in the ECM - Fibrous proteins: Collagen, fibrin, elastin. - Fibrous proteins provide structural/mechanical cues to direct cell behavior. Soluble signals are sequestered by proteoglycans and bind to cell surface receptors to direct cell fate. Integrins (transmembrane receptors) bind to adhesive proteins. - Adhesive proteins: Fibronectin, laminin. - ECM degradation enzymes (e.g., matrix metalloproteinases, serine proteinases, plasmin). Fibrous Proteins - Water-insoluble, extended molecules with structural functions. - Composed of specific amino acids that combine into regular helical or sheet-like secondary structures. - In contrast, globular proteins have more compact structures with secondary, tertiary, and sometimes quaternary structures. Collagens: Major Proteins in the ECM - Most abundant proteins in mammals, form fibers resistant to shearing. - Molecule: a helix of three α chains, rich in proline and glycine; proline produces a kink, glycine contributes to compactness. - Lysine side groups allow covalent bonds between strands (fiber formation). - Fibrillar collagens assemble into collagen fibers. - Types IX and XII collagens influence fibril interactions. Collagen Synthesis - Collagens enter the ER during synthesis, have signal peptides and propeptides at both ends. - Propeptides guide helical molecule formation in the ER and prevent collagen fibrils inside the cells. - Hydroxylation of prolines and lysines; procollagen forms in the ER. - After secretion, propeptides are removed, and collagens assemble into fibrils, strengthened by covalent crosslinks between lysines. Fibril-associated Collagens (IX and XII) - Guide collagen fibril formation, with flexible molecules due to non-helical domains. - Retain their propeptides after secretion. - Do not aggregate to form fibrils; bind to the surface of other collagen fibrils. Osteogenesis Imperfecta - Genetic disorders characterized by bone fragility, fractures, blue sclera, and loose joints. - Caused by mutations in COL1A1 and COL1A2 genes, which encode proteins involved in type I collagen assembly. - Reduced/modified type I collagen causes brittle bones. Elastin - Enables skin, arteries, and lungs to stretch and recoil. - Hydrophobic, rich in proline and glycine, non-glycosylated, with some hydroxyproline but no hydroxylysine. - Alternating segments: hydrophobic (elastic properties) and α-helices (crosslinks). - Tropoelastin is the precursor, secreted into the ECM, crosslinked through lysines after secretion. MODULE 21 Adhesive Proteins - Glycoproteins that organize the ECM and link cells to the ECM. - Fibronectin: Principal adhesive protein in connective tissues. - Laminin: Principal adhesive protein in epithelial tissues. - Multiple binding domains link cells and ECM components (e.g., proteoglycans, collagens). Fibronectin - Insoluble, cell-surface glycoprotein with two subunits joined by disulfide bonds. Plasma fibronectin is soluble in body fluids. - Subunits contain domains separated by flexible regions. Main type binds to integrins. - One gene with ~50 exons, RNA is alternatively spliced. - Actin filaments inside cells promote assembly and orientation of secreted fibronectin into fibrils. ECM Influences Cell Shape and Fate - ECM influences the cytoskeleton: Cancer cells make less fibronectin, adhere poorly, fail to flatten or develop organized actin filaments. - Actin filaments promote assembly and influence fibronectin fibrils. - ECM creates oriented structures from cell to cell. - Attachment dependence (anchorage dependence) is mediated by integrins. ECM and Cell Migration - ECM degradation occurs during migration (cancer cells, leukocytes). - ECM degraded by matrix metalloproteases, serine proteases (Ca2+- or Zn2+-dependent). - ECM proteolysis assists migration by clearing paths, exposing binding sites, promoting detachment, and releasing signals. - Many proteases secreted as inactive precursors, activated locally. - Protease action confined by secreted inhibitors. ECM Remodeling - ECM is dynamic, continuously remodeled through degradation of old proteins and synthesis of new ones. - High turnover: ECM degradation releases fragments into circulation, and new proteins accumulate. - Fibrotic diseases involve increased ECM formation and degradation, releasing signature protein fragments. Putting It Together - Fiber-forming proteins (collagen, elastin) strengthen the matrix and provide surfaces for cells to adhere to ECM. - Elastins form networks that stretch and recoil for elasticity. - Fibrillar collagens are triple-stranded helical molecules that form fibrils, while fibril-associated collagens influence fibril interactions. - Fibronectin and laminin organize ECM and help cells adhere to it. - ECM influences cell behavior by binding to integrins, activating intracellular signaling. - Matrix components degraded by proteolytic enzymes (e.g., matrix metalloproteases, serine proteases).