4 nots - 1 September 17, 2008 Verbatim text (italicized) is...

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1 September 17, 2008 Lecture 4 Verbatim text (italicized) is primarily from Hay E. Hay E (Ed) Cell Biol of Extracellular Matrix, 2nd Ed. 1991 Procollagen processing As discussed in the previous class, Type I collagen procollagen contains an additional 150 amino acids at the N-terminus and 250 amino acids at the C-terminus. Removal of N-terminal C-terminal propeptides in the extracellular space is carried out by Zn 2+ - dependent plasma membrane-associated metalloproteinases (MMPs). ADAMTS-3 is the principal N-peptidase for cartilage whereas ADAMTS-2 and -14 is the predominant enzyme found in skin and other connective tissues. Cleavage of the C-terminal globular domain is carried out by BMPs. Removal of the C-prodomain domain is of particular importance since it decreases the solubility of the resultant collagen molecules – hence reducing the critical concentration required for fibril assembly. Removal of the C- propeptide therefore triggers fibrils assembly. The short non-helical regions at the N- and C-terminal are called telopeptides . Hay E. Hay E (Ed) Cell Biol of Extracellular Matrix, 2nd Ed. 1991 “The extracellular sequence for the removal of the polypeptides involves first the removal of the removal of all three chains in the NH 2 -terminal extension as a single piece. This procollagen intermediate (s) with only the NH2-terminal propeptide removed is termed P C -collagen , indicating that it is a procollagen form with an intact C-terminal extension but no N-terminal one. Subsequently, the C-terminal extensions are also removed en bloc, resulting in a completely processed collagen molecule. In the normal sequence of conversion, molecules with only the N-terminal propeptide intact are usually not found, as this is the first to be removed. Such molecules, called P N -collagen , are the product of a genetic abnormality such as dermatosparaxis disease, in which the skin is extremely fragile and easily torn” . This information must be taken with caution in light that we now know that differential processing of the N-terminus is one of the strategies used by cells to regulate fibril size. A key point is that the C-terminal propeptide must be removed for fibrillogenesis to begin. Fibrillogenesis: lateral associations and covalent cross-linking Fibril formation begins with the lateral interactions/associations of adjacent molecules, displaced by approximately ¼ of their length (67-70 nm or 1D) (typical quarter- staggered fibril array). Each collagen molecule is 4.3 D units long. The “hole” region is 0.6 D with the overlap 0.4D. The staggered array produces a striated effect went the fibrils are stained with electron dense and viewed in the electron microscope. Adjacent collagen molecules are orientated head to tail or N-terminus to C-terminus. Accompanying fibril formation is the oxidation of specific N- and C-terminal telopeptide
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4 nots - 1 September 17, 2008 Verbatim text (italicized) is...

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