Tyrosine residues mediate fibril formation in a dynamic light chain dimer interface

Ara Celi DiCostanzo, James R. Thompson, Francis C. Peterson, Brian F. Volkman, Marina Ramirez-Alvarado

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Light chain amyloidosis is an incurable protein misfolding disease where monoclonal immunoglobulin light chains misfold and deposit as amyloid fibrils, causing organ failure and death. Previously, we determined that amyloidogenic light chains AL-09 and AL-103 do not form fibrils at pH 10 (tyrosine pK a). There are three tyrosine residues (32, 91, and 96) clustered in the dimer interface, interacting differently in the two light chain proteins due to their two different dimer conformations. These tyrosines may be ionized at pH 10, causing repulsion and inhibiting fibril formation. Here, we characterize single and double Tyr-to-Phe mutations in AL-09 and AL-103. All AL-09 Tyr-to-Phe mutants form fibrils at pH 10, whereas none of the AL-103 mutants form fibrils at pH 10. NMR studies suggest that although both AL-09 and AL-103 present conformational heterogeneity, only AL-09 favors dimer conformations where tyrosine residues mediate crucial interactions for amyloid formation.

Original languageEnglish (US)
Pages (from-to)27997-28006
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number33
DOIs
StatePublished - Aug 10 2012

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Dimers
Tyrosine
Light
Amyloid
Conformations
Proteostasis Deficiencies
Immunoglobulin Light Chains
Amyloidosis
Proteins
Deposits
Nuclear magnetic resonance
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Tyrosine residues mediate fibril formation in a dynamic light chain dimer interface. / DiCostanzo, Ara Celi; Thompson, James R.; Peterson, Francis C.; Volkman, Brian F.; Ramirez-Alvarado, Marina.

In: Journal of Biological Chemistry, Vol. 287, No. 33, 10.08.2012, p. 27997-28006.

Research output: Contribution to journalArticle

DiCostanzo, Ara Celi ; Thompson, James R. ; Peterson, Francis C. ; Volkman, Brian F. ; Ramirez-Alvarado, Marina. / Tyrosine residues mediate fibril formation in a dynamic light chain dimer interface. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 33. pp. 27997-28006.
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