Lecture 4 Fibrillogenesis, EDS and CIV Sept 21, 2016

Lecture 4 Fibrillogenesis, EDS and CIV Sept 21, 2016 -...

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1 Lecture Topics L1 Sept 1 2 Intracellular processing and secretion of ECM molecules L2 Sept Molecular organization and classification of collagens: fibril-forming collagens. Type I collagen and connective tissue defects due to the improper assem14bly of type I collagen In the ER: scurvy and osteogenesis imperfecta. L3 Sept 19 Supramolecular assembly and cross-linking of type I collagen molecules. Dermatosparaxis disease L4 Sept 21 Connective tissue collagen defects: Ehlers-Danlos syndrome Basal laminae/basement membranes: network-forming type IV collagen Role of basal laminae in epithelial morphogenesis: focus on collagen IV. Role of collagen IV in kidney filtration Type VII collagens and anchoring fibrils in the dermal-epidermal junction zone and epidermolysis bullosa FACIT collagens and epiphyseal dysplasia Minicollagens and jelly fish nematocysts
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2 Cell-matrix interactions in fibripositors: integrins and actomyosin pulling forces
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3 The subunit structure of an integrin cell-surface matrix receptor Matrix binding Matrix molecule or polymer Integrin heterodimer: α and β subunits 24 integrins heterodimers: derived from a combination 18 α subunits 8 β subunits in mammals Protein adapters, scaffolds, kinases, Monomeric GTPases, etc.
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Structural Domains of Collagen Receptors DDRs: Discoidin Domain Receptors- DDR1 & DDR2 Tyrosine Kinase activity No enzymatic activity Integrins α 1 β 1 and α 10 β 1 prefer ColIV α 2 β 1 and α 11 β 1 prefer fibrillar collagens GPVI is an activating receptor on platelets LAIR-1 inhibitory receptor on immune cells
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The position and amino acid sequence of six–amino acid binding motifs for integrins & the discoidin domain receptors (DDRs) are indicated by narrow blue and orange bars, respectively Integrin-binding sites DDR-binding site Distribution of receptor-binding sites on collagens I, II, and III. O = HO-Proline
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Selected intracellular events induced by discoidin domain receptor 1 (DDR1) binding to collagen. Signaling cross-talk between collagen-binding receptors Do not memorize ColI receptor
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7 F-actin filaments Myosin II motor Adaptor/linker complex Plasma membrane Collagen fibril Pulling force Cells exert tractional forces on adhesive substrata integrins intracellular extracellular Signal transduction molecules not shown
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8 An in vitro experiment demonstrating how the matrix cells secrete can in turn serve as an adhesive substratum for directional cell migration. Migrating fibroblasts Heart fibroblast migration on collagen Embryonic heart explant Collagen gel Aligned collagen fibrils Embryonic heart explants cultured on a collagen gel For 4 days A mixture of cardiomyocytes & fibroblasts
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9 The shaping of the extracellular matrix by cells Dense track of aligned collagens has formed between the explants – probably mainly due to pulling/tensional forces by fibroblast cells Pages 1101-1102 Migrating fibroblasts The aligned collagen fibers serve as an adhesive substratum that promote fibroblast cell migration Aligned collagen fibrils
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10 Cell-matrix interactions in fibripositors: Integrins and actomyosin pulling forces Classical EDS: mutations in type I and V collagens
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