Understanding the complex mechanisms of β2-microglobulin amyloid assembly

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Abstract

Several protein misfolding diseases are associated with the conversion of native proteins into ordered protein aggregates known as amyloid. Studies of amyloid assemblies have indicated that non-native proteins are responsible for initiating aggregation in vitro and in vivo. Despite the importance of these species for understanding amyloid disease, the structural and dynamic features of amyloidogenic intermediates and the molecular details of how they aggregate remain elusive. This review focuses on recent advances in developing a molecular description of the folding and aggregation mechanisms of the human amyloidogenic protein β ₂-microglobulin under physiologically relevant conditions. In particular, the structural and dynamic properties of the non-native folding intermediate I _T and its role in the initiation of fibrillation and the development of dialysis-related amyloidosis are discussed.

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Most cited references 139

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Amyloid formation by globular proteins under native conditions.

Fabrizio Chiti, Christopher Dobson (2009)

The conversion of proteins from their soluble states into well-organized fibrillar aggregates is associated with a wide range of pathological conditions, including neurodegenerative diseases and systemic amyloidoses. In this review, we discuss the mechanism of aggregation of globular proteins under conditions in which they are initially folded. Although a conformational change of the native state is generally necessary to initiate aggregation, we show that a transition across the major energy barrier for unfolding is not essential and that aggregation may well be initiated from locally unfolded states that become accessible, for example, via thermal fluctuations occurring under physiological conditions. We review recent evidence on this topic and discuss its significance for understanding the onset and potential inhibition of protein aggregation in the context of diseases.

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Amyloidosis.

Mark Pepys (2006)

Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils, derived from aggregation of misfolded, normally soluble, protein. About 23 different unrelated proteins are known to form amyloid fibrils in vivo, which share a pathognomonic structure although they are associated with clinically distinct conditions. Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls, and connective tissue, is usually fatal and is the cause of about one per thousand deaths in developed countries. This rarity and the variable involvement of different organs and tissues are often responsible for missed or delayed diagnosis, and amyloidosis remains a considerable clinical challenge. However, recent elucidation of important aspects of pathogenesis, as well as developments in diagnosis, monitoring, and treatment, have greatly improved outcomes, especially when patients are managed in specialist centers.

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Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis.

D Booth, M Sunde, V Bellotti … (1997)

Tissue deposition of soluble proteins as amyloid fibrils underlies a range of fatal diseases. The two naturally occurring human lysozyme variants are both amyloidogenic, and are shown here to be unstable. They aggregate to form amyloid fibrils with transformation of the mainly helical native fold, observed in crystal structures, to the amyloid fibril cross-beta fold. Biophysical studies suggest that partly folded intermediates are involved in fibrillogenesis, and this may be relevant to amyloidosis generally.

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Author and article information

Journal

Journal ID (nlm-ta): FEBS J

Journal ID (publisher-id): febs

Title: The Febs Journal

Publisher: Blackwell Publishing Ltd

ISSN (Print): 1742-464X

ISSN (Electronic): 1742-4658

Publication date (Print): October 2011

Volume: 278

Issue: 20

Pages: 3868-3883

Affiliations

[1 ]simpleDepartment of Biochemistry, Brandeis University Waltham, MA, USA

[2 ]simpleAstbury Centre for Structural Molecular Biology and Institute of Molecular Cellular Biology, University of Leeds UK

Author notes

S. E. Radford, Astbury Centre for Structural Molecular Biology and Institute of Molecular Cellular Biology, University of Leeds, Leeds LS2 9JT, UK Fax: +44 113 343 7486 Tel: +44 113 343 3170 E-mail: s.e.radford@ 123456leeds.ac.uk

T. Eichner, Department of Biochemistry, Brandeis University, Waltham, MA 02454, USA Fax: +1 781 736 2316 Tel: +1 781 736 2326 E-mail: teichner@ 123456brandeis.edu

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Article

DOI: 10.1111/j.1742-4658.2011.08186.x

PMC ID: 3229708

PubMed ID: 21595827

SO-VID: d597bcd3-2827-4e4e-8749-29f9b1e55c3b

License:

Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

History

Date received : 05 April 2011

Date revision received : 11 May 2011

Date accepted : 13 May 2011

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