1qmb

From Proteopedia

Revision as of 15:47, 18 December 2007

CLEAVED ALPHA-1-ANTITRYPSIN POLYMER

Overview

The function of the serpins as proteinase inhibitors depends on their, ability to insert the cleaved reactive centre loop as the fourth strand in, the main A beta-sheet of the molecule upon proteolytic attack at the, reactive centre, P1-P1'. This mechanism is vulnerable to mutations which, result in inappropriate intra- or intermolecular loop insertion in the, absence of cleavage. Intermolecular loop insertion is known as serpin, polymerisation and results in a variety of diseases, most notably liver, cirrhosis resulting from mutations of the prototypical serpin, alpha1-antitrypsin. We present here the 2.6 A structure of a polymer of, alpha1-antitrypsin cleaved six residues N-terminal to the reactive centre, P7-P6 (Phe352-Leu353). After self insertion of P14 to P7, intermolecular, linkage is affected by insertion of the P6-P3 residues of one molecule, into the partially occupied beta-sheet A of another. This results in an, infinite, linear polymer which propagates in the crystal along a 2-fold, screw axis. These findings provide a framework for understanding the, uncleaved alpha1-antitrypsin polymer and fibrillar and amyloid deposition, of proteins seen in other conformational diseases, with the ordered array, of polymers in the crystal resulting from slow accretion of the cleaved, serpin over the period of a year.

Disease

Known diseases associated with this structure: Emphysema OMIM:[107400], Emphysema-cirrhosis OMIM:[107400], Hemorrhagic diathesis due to antithrombin Pittsburgh OMIM:[107400], Pulmonary disease, chronic obstructive, susceptibility to OMIM:[107400]

About this Structure

1QMB is a Protein complex structure of sequences from Homo sapiens. Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

A 2.6 A structure of a serpin polymer and implications for conformational disease., Huntington JA, Pannu NS, Hazes B, Read RJ, Lomas DA, Carrell RW, J Mol Biol. 1999 Oct 29;293(3):449-55. PMID:10543942

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