4 - Sept 17 , 2008 Lecture 4 Extracellular Processing and...

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1 Sept 17 , 2008 Lecture 4 Extracellular Processing and the Supramolecular Assembly of Type I Collagen Collagen Defects: Ehlers-Danlos Syndrome
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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
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3 Type Class alpha chain gene Length of collagenous domains (human) α -chain composition Main distribution Supramolecular assembly Genetic Disease I fibrillar 1(I) COL1A1 1014 1,1,2 ubiquitous major component of fibrils Osteogenesis imperfecta, osteoporosis, Ehlers-Danlos syndrome (EDS) types VIIA, VIIB 2(I) COL1A2 1014 II fibrillar 1(II) COL2A1 1017 111 hyaline cartilage major component of fibrils some types of chondrodyspla sias III fibrillar 1(III) COL3A1 1029 111 same as type I, little in bone and tendon minor component of fibrils EDS IV, aortic aneurysms Classification of Collagens Nomenclature: α -chain composition α 1(I) 2 α 2(I) Heterotrimer α 1(II) 3 Homotrimer Type I collagen will be used as the prototype for fibrillar collagens
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4 67 nm Golgi Hsp47 Segment long spacing ??? Propeptide cleavage Self-association Collagen fibril Endoplasmic reticulum α 1 α 1 α 2 Extracellular compartment Persikov and Brodsky (2002) PNAS 99:1101-1103 A schematic of the biosynthesis of collagen from ER to the extracellular space Triple helix formation is biosynthetically determined by C-propeptide Type I collagen Fiber
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5 Fibroblast Cells electron micrograph (44,000X) Collagen molecules assemble into fibrils that are stabilized by lysyl oxidase cross-links 4 3 2 ER Golgi Collagen Biosynthesis Pathway
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6 Extracellular cross-linking of fibrillar collagen
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7 Aldol cross-link Spontaneous? Highly reactive aldehyde derivatives Lysyl oxidase (LO) Side-by-side interactions between collagen molecules is stabilized by aldol cross-links between two lysine side chains Cross-links are catalyzed by the extracellular enzyme lysyl oxidase H H BMP2 (an MMP) Pro-LO Æ LO deamination Reactive aldehydes can react with each other or with other Lys or HO-Lys
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8 Cross-links formed between modified lysine side chains within a collagen fibril Most of the cross-links are from within the non-helical telopeptide domains Pages 1096-1101
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9 Right-handed triple-stranded helical collagen molecule The structure of fibrillar collagens: molecule Æ fibrils Æ fibers Collagen fibril (Quarter
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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- Toronto.

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4 - Sept 17 , 2008 Lecture 4 Extracellular Processing and...

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