A single mutation promotes amyloidogenicity through a highly promiscuous dimer interface

Francis C. Peterson, Elizabeth M. Baden, B. A L Owen, Brian F. Volkman, Marina Ramirez-Alvarado

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Light chain amyloidosis is a devastating protein misfolding disease characterized by the accumulation of amyloid fibrils that causes tissue damage and organ failure. These fibrils are composed of monoclonal light chain protein secreted from an abnormal proliferation of bone marrow plasma cells. We previously reported that amyloidogenic light chain protein AL-09 adopts an altered dimer while its germline protein (κI O18/O8) forms a canonical dimer observed in other light chain crystal structures. In solution, conformational heterogeneity obscures all NMR signals at the AL-09 and κI O18/O8 dimer interfaces, so we solved the nuclear magnetic resonance structure of two related mutants. AL-09 H87Y adopts the normal dimer interface, but the κI Y87H solution structure presents an altered interface rotated 180° relative to the canonical dimer interface and 90° from the AL-09 arrangement. Our results suggest that promiscuity in the light chain dimer interface may promote new intermolecular contacts that may contribute to amyloid fibril structure.

Original languageEnglish (US)
Pages (from-to)563-570
Number of pages8
JournalStructure
Volume18
Issue number5
DOIs
StatePublished - May 2010

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Light
Mutation
Amyloid
Proteostasis Deficiencies
Proteins
Amyloidosis
Plasma Cells
Bone Marrow Cells
Magnetic Resonance Spectroscopy

Keywords

  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

A single mutation promotes amyloidogenicity through a highly promiscuous dimer interface. / Peterson, Francis C.; Baden, Elizabeth M.; Owen, B. A L; Volkman, Brian F.; Ramirez-Alvarado, Marina.

In: Structure, Vol. 18, No. 5, 05.2010, p. 563-570.

Research output: Contribution to journalArticle

Peterson, Francis C. ; Baden, Elizabeth M. ; Owen, B. A L ; Volkman, Brian F. ; Ramirez-Alvarado, Marina. / A single mutation promotes amyloidogenicity through a highly promiscuous dimer interface. In: Structure. 2010 ; Vol. 18, No. 5. pp. 563-570.
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