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Nokwe, C.N.* ; Hora, M. ; Zacharias, M.* ; Yagi, H.* ; Peschek, J.* ; Reif, B. ; Goto, Y.* ; Buchner, J.*

A stable mutant predisposes antibody domains to amyloid formation through specific non-native interactions.

J. Mol. Biol. 428, 1315-1332 (2016)
Postprint DOI PMC
Open Access Green
The aggregation of mostly antibody light chain variable (VL) domains into amyloid fibrils in various tissues is the main cause of death in systemic amyloid light chain amyloidosis. Point mutations within the domain are important to shift the VL into the fibrillar pathway. But why and how only some site-specific mutations achieve this still remains elusive. We show here that both destabilizing and surprisingly stable mutants readily predispose an amyloid resistant VL domain to amyloid formation. The decreased thermodynamic stability of the destabilizing mutant results in the accumulation of non-native intermediates that readily populate the amyloid state. Interestingly, the stable mutants establish site-specific non-native interactions with especially nearby serine/threonine residues that unexpectedly do not affect the folding behavior of the VL domain but rather readily induce and stabilize the fibril structure, a previously unrecognized mechanism. These findings provide a new concept for the molecular mechanism of amyloid fibril formation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Immunoglobulin Fold ; Antibody Amyloid ; Domain Stability ; Point Mutations ; Protein Folding And Aggregation Disease; Immunoglobulin Light-chains; Bence-jones Proteins; Fibril Formation; Deposition Disease; Molten Globule; Systemic Amyloidoses; Crystal-structure; Variable Domains; Peptide Gnnqqny; Folding Pathway
ISSN (print) / ISBN 0022-2836
e-ISSN 1089-8638
Zeitschrift Journal of Molecular Biology
Quellenangaben Band: 428, Heft: 6, Seiten: 1315-1332 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)