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Published online before print February 6, 2004, 10.1110/ps.03445704
Protein Science (2004), 13:797-809. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Increase in the conformational flexibility of {beta}2-microglobulin upon copper binding: A possible role for copper in dialysis-related amyloidosis

James Villanueva1,4,5, Masaru Hoshino1,4, Hidenori Katou1, József Kardos1, Kazuhiro Hasegawa2, Hironobu Naiki2,3 and Yuji Goto1,3

1 Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan
2 Department of Pathology, Fukui Medical University, Matsuoka, Fukui 910-1193, Japan
3 CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan

(RECEIVED September 19, 2003; FINAL REVISION October 24, 2003; ACCEPTED November 10, 2003)



Abstract

A key pathological event in dialysis-related amyloidosis is the fibril formation of {beta}2-microglobulin ({beta}2-m). Because {beta}2-m does not form fibrils in vitro, except under acidic conditions, predisposing factors that may drive fibril formation at physiological pH have been the focus of much attention. One factor that may be implicated is Cu2+ binding, which destabilizes the native state of {beta}2-m and thus stabilizes the amyloid precursor. To address the Cu2+-induced destabilization of {beta}2-m at the atomic level, we studied changes in the conformational dynamics of {beta}2-m upon Cu2+ binding. Titration of {beta}2-m with Cu2+ monitored by heteronuclear NMR showed that three out of four histidines (His13, His31, and His51) are involved in the binding at pH 7.0. 1H-15N heteronuclear NOE suggested increased backbone dynamics for the residues Val49 to Ser55, implying that the Cu2+ binding at His51 increased the local dynamics of {beta}-strand D. Hydrogen/deuterium exchange of amide protons showed increased flexibility of the core residues upon Cu2+ binding. Taken together, it is likely that Cu2+ binding increases the pico- to nanosecond fluctuation of the {beta}-strand D on which His51 exists, which is propagated to the core of the molecule, thus promoting the global and slow fluctuations. This may contribute to the overall destabilization of the molecule, increasing the equilibrium population of the amyloidogenic intermediate.

Keywords: Amyloid fibrils; copper binding; dialysis-related amyloidosis; heteronuclear NMR; hydrogen/deuterium exchange; {beta}2-microglobulin; protein folding/misfolding

Abbreviations: {beta}2-m, {beta}2-microglobulin • CD, circular dichroism • H/D, hydrogen/deuterium • HSQC, heteronuclear single quantum coherence • NMR, nuclear magnetic resonance • NOE, {eta}, nuclear Overhauser effect • R1, longitudinal relaxation rates • TOCSY, total correlation spectroscopy

Reprint requests to: Yuji Goto, Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan; e-mail: ygoto{at}protein.osaka-u.ac.jp; fax: 081-6-6879-8616.

Supplemental material: See www.proteinscience.org

4 These authors contributed equally to this work.

5 Present address: Institute of Chemistry, University of the Philippines, Diliman, Quezon City, Philippines.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03445704.


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