Structural insights into the role of mutations in amyloidogenesis

Elizabeth M. Baden, Edward G. Randles, Awo K. Aboagye, James R. Thompson, Marina Ramirez-Alvarado

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Mechanisms of amyloidogenesis are not well understood, including potential structural contributions of mutations in the process. Our previous research indicated that the dimer interface of amyloidogenic immunoglobulin light chain protein AL-09 is twisted 90° relative to the protein from its germline sequence, κI O18/O8. Here we report a systematic restoration of AL-09 to its germline sequence by mutating the non-conservative somatic mutations located in the light chain dimer interface. Among these mutants, we find a correlation between increased thermodynamic stability and an increase in the lag time for fibril formation. The restorative mutant AL-09 H87Y completes the trifecta and restores the dimer interface observed in κI O18/O8, emphasizing the potential importance of the structural integrity of these proteins to protect against amyloidogenicity. We also find that adding amyloidogenic mutations into the germline protein illustrates mutational cooperativity in promoting amyloidogenesis.

Original languageEnglish (US)
Pages (from-to)30950-30956
Number of pages7
JournalJournal of Biological Chemistry
Volume283
Issue number45
DOIs
StatePublished - Nov 7 2008

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Dimers
Mutation
Proteins
Immunoglobulin Light Chains
Germ-Line Mutation
Structural integrity
Thermodynamics
Restoration
Thermodynamic stability
Light
Research

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Structural insights into the role of mutations in amyloidogenesis. / Baden, Elizabeth M.; Randles, Edward G.; Aboagye, Awo K.; Thompson, James R.; Ramirez-Alvarado, Marina.

In: Journal of Biological Chemistry, Vol. 283, No. 45, 07.11.2008, p. 30950-30956.

Research output: Contribution to journalArticle

Baden, Elizabeth M. ; Randles, Edward G. ; Aboagye, Awo K. ; Thompson, James R. ; Ramirez-Alvarado, Marina. / Structural insights into the role of mutations in amyloidogenesis. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 45. pp. 30950-30956.
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