Increase in the conformational flexibility of β2‐microglobulin upon copper binding: A possible role for copper in dialysis‐related amyloidosis

• DOI: 10.1110/ps.03445704
• Publication Date: 2004-02-10T01:34:21Z
• Authors: James Villanueva; Masaru Hoshino; Hidenori Katou; József Kardos; Kazuhiro Hasegawa; Hironobu Naiki; Yuji Goto
• Keywords: Heteronuclear molecule; BETA (programming language)

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 vitro, except under acidic conditions, predisposing factors that may drive at physiological pH have been focus much attention. One factor be implicated Cu(2+) binding, which destabilizes native state and thus stabilizes amyloid precursor. To address Cu(2+)-induced destabilization atomic level, we studied changes conformational dynamics upon binding. Titration with monitored by heteronuclear NMR showed three out four histidines (His13, His31, His51) are involved binding 7.0. (1)H-(15)N NOE suggested increased backbone for residues Val49 to Ser55, implying His51 local beta-strand D. Hydrogen/deuterium exchange amide protons flexibility core Taken together, it likely increases pico- nanosecond fluctuation D on exists, propagated molecule, promoting global slow fluctuations. This contribute overall increasing equilibrium population amyloidogenic intermediate.