A Stable Mutant Predisposes Antibody Domains to Amyloid Formation through Specific Non-Native Interactions

Cardine N. Nokwe, Manuel Hora, Martin Zacharias, Hisashi Yagi, Jirka Peschek, Bernd Reif, Yuji Goto, Johannes Buchner

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1315-1332
Number of pages18
JournalJournal of Molecular Biology
Volume428
Issue number6
DOIs
StatePublished - 27 Mar 2016

Keywords

  • antibody amyloid
  • domain stability
  • immunoglobulin fold
  • point mutations
  • protein folding and aggregation disease

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