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A regulatable switch mediates self-association in an immunoglobulin fold

β-2 microglobulin (β2m) is a globular protein that self-associates into fibrillar amyloid deposits in patients undergoing hemodialysis therapy. Formation of these β-sheet–rich assemblies is a fundamental property of polypeptides that can be triggered by diverse conditions. For β2m, oligomerization i...

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Detalles Bibliográficos
Autores principales: Calabrese, Matthew F, Eakin, Catherine M, Wang, Jimin M, Miranker, Andrew D
Formato: Texto
Lenguaje:English
Publicado: 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680708/
https://www.ncbi.nlm.nih.gov/pubmed/19172750
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author Calabrese, Matthew F
Eakin, Catherine M
Wang, Jimin M
Miranker, Andrew D
author_facet Calabrese, Matthew F
Eakin, Catherine M
Wang, Jimin M
Miranker, Andrew D
author_sort Calabrese, Matthew F
collection PubMed
description β-2 microglobulin (β2m) is a globular protein that self-associates into fibrillar amyloid deposits in patients undergoing hemodialysis therapy. Formation of these β-sheet–rich assemblies is a fundamental property of polypeptides that can be triggered by diverse conditions. For β2m, oligomerization into pre-amyloidogenic states occurs in specific response to coordination by Cu(2+). Here we report the basis for this self-association at atomic resolution. Metal is not a direct participant in the molecular interface. Rather, binding results in distal alterations enabling the formation of two new surfaces. These interact to form a closed hexameric species. The origins of this include isomerization of a buried and conserved cis-proline previously implicated in the β2m aggregation pathway. The consequences of this isomerization are evident and reveal a molecular basis for the conversion of this robust monomeric protein into an amyloid-competent state.
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spelling pubmed-26807082009-05-12 A regulatable switch mediates self-association in an immunoglobulin fold Calabrese, Matthew F Eakin, Catherine M Wang, Jimin M Miranker, Andrew D Nat Struct Mol Biol Article β-2 microglobulin (β2m) is a globular protein that self-associates into fibrillar amyloid deposits in patients undergoing hemodialysis therapy. Formation of these β-sheet–rich assemblies is a fundamental property of polypeptides that can be triggered by diverse conditions. For β2m, oligomerization into pre-amyloidogenic states occurs in specific response to coordination by Cu(2+). Here we report the basis for this self-association at atomic resolution. Metal is not a direct participant in the molecular interface. Rather, binding results in distal alterations enabling the formation of two new surfaces. These interact to form a closed hexameric species. The origins of this include isomerization of a buried and conserved cis-proline previously implicated in the β2m aggregation pathway. The consequences of this isomerization are evident and reveal a molecular basis for the conversion of this robust monomeric protein into an amyloid-competent state. 2008-09 /pmc/articles/PMC2680708/ /pubmed/19172750 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Calabrese, Matthew F
Eakin, Catherine M
Wang, Jimin M
Miranker, Andrew D
A regulatable switch mediates self-association in an immunoglobulin fold
title A regulatable switch mediates self-association in an immunoglobulin fold
title_full A regulatable switch mediates self-association in an immunoglobulin fold
title_fullStr A regulatable switch mediates self-association in an immunoglobulin fold
title_full_unstemmed A regulatable switch mediates self-association in an immunoglobulin fold
title_short A regulatable switch mediates self-association in an immunoglobulin fold
title_sort regulatable switch mediates self-association in an immunoglobulin fold
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680708/
https://www.ncbi.nlm.nih.gov/pubmed/19172750
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