1qmb
From Proteopedia
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==Overview== | ==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. | 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. | ||
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| + | ==Disease== | ||
| + | Known diseases associated with this structure: Emphysema OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107400 107400]], Emphysema-cirrhosis OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107400 107400]], Hemorrhagic diathesis due to antithrombin Pittsburgh OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107400 107400]], Pulmonary disease, chronic obstructive, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107400 107400]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: serpin]] | [[Category: serpin]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:54:45 2007'' |
Revision as of 16:48, 12 November 2007
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CLEAVED ALPHA-1-ANTITRYPSIN POLYMER
Contents |
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. Structure known Active Site: P7. 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
Page seeded by OCA on Mon Nov 12 18:54:45 2007
Categories: Homo sapiens | Protein complex | Carrell, R.W. | Hazes, B. | Huntington, J.A. | Lomas, D.A. | Pannu, N.S. | Read, R.J. | Antitrypsin | Cleaved | Polymer | Serpin
