Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 428, Issue 6, Pages 1315-1332Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2016.01.015
Keywords
protein folding and aggregation disease; antibody amyloid; point mutations; domain stability; immunoglobulin fold
Categories
Funding
- Deutsche Forschungsgemeinschaft
- Bundesministerium fuer Bildung and Forschung within the network GERAMY
- collaborative research center [SFB 1035]
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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. (C) 2016 Elsevier Ltd. All rights reserved.
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