6 - 1 Sept 24, 2008 Lecture 6 The role of basal laminae in...

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Unformatted text preview: 1 Sept 24, 2008 Lecture 6 The role of basal laminae in epithelial morphogenesis & kidney filtration 2 Lecture Topics and Test Dates (1) Sept 8 Introduction (2) Sept 10 Intracellular processing and transport of ECM molecules Molecular organization of collagens, classification Fibrillar collagens: type I collagen - prototype (3) Sept 15 Connective tissue defects due to the improper assembly of type I collagen in the ER: scurvy and osteogenesis imperfecta (4) Sept 17 Extracellular processing and the supramolecular assembly of type I collagen Collagen defects: Ehlers-Danlos syndrome (EDS) (5) Sept 22 EDS continued Basal laminae/basement membranes: network-forming collagen IV {6) Sept 24 Role of basal laminae in epithelial morphogenesis and kidney filtration (7) Sept 29 Type VII collagens and anchoring fibrils in the dermal-epidermal junction zone 3 Monomer (single -chain) ~1400 a.a. NC1 ~230 a.a. 7S NC1 interactions initiate protomer formation Protomer: a trimer of a-chains Assembly in the Golgi? Protomer Dimerization NC1 hexamer Nucleation and subsequent propagation of triple helix formation in a zipper-like fashion NC1 interactions mediated by interchain hydrophobic interactions and H-bonding and domain-swapping that clamp the trimeric complex together Dimer Modified fig. from Raghu Kalluri Nature Reviews Cancer 3, 422-433 (June 2003) Secretion 4 2 1 1 2 1 1 4 5 3 4 3 5 Assembly of type IV collagen hexamers 1 2 2 protomers (embryonic and broadly distributed) 3 4 5 protomers (e.g. kidney glomerular BM, lens capsule, cornea and retina BM) Chain selection by non-covalent interactions The NC1 domain not only initiates chain assembly into protomers, but also governs chain selection to ensure proper isoform combinations are assembled. Protomers dimerize via their C-terminal NC1 domain to form hexamer Modified fig. from Raghu Kalluri Nature Reviews Cancer 3, 422-433 (June 2003) 5 Intermediate non-covalently bonded type IV collagen tetramer, followed by stabilization via disulfide bonds and lysine-derived cross-linking Dimer 7S Domain NC1 hexamer Supramolecular organization into a covalently crosslinked laterally associated network Supramolecular assembly of type IV collagen Inter-helical disulfide cross-linked Modified fig. from Raghu Kalluri Nature Reviews Cancer 3, 422-433 (June 2003) In extracellular compartments 6 6 2 1 1 5 5 The 1 2 5 6 network Prominent in tissues that undergo rhythmic elastic changes in size, e.g. in the basement membranes surrounding visceral Smooth muscle of esophagus, stomach, small intestines and colon. Also found in BMs of gastrourinaty tracks including the bladder, ureter and uterus and epidermal BM Extracellular Matrix in Development and Disease: Advances in Developmental Biology, Vol 15, Ed. Jeffery Miner, 2005, Elsvier, p25 Function unknown. 7 A model of the molecular structure of basal laminae 8 Early stages of mouse development Activation of E-cadherin (Cell-cell Adhesion) Source of embryonic stem cells Zona Pellucida 9...
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6 - 1 Sept 24, 2008 Lecture 6 The role of basal laminae in...

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