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Tyrosine residues mediate fibril formation in a dynamic light chain dimer interface. J Biol Chem 2012 Aug 10;287(33):27997-8006

Date

06/29/2012

Pubmed ID

22740699

Pubmed Central ID

PMC3431636

DOI

10.1074/jbc.M112.362921

Scopus ID

2-s2.0-84865034948   16 Citations

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.

Author List

DiCostanzo AC, Thompson JR, Peterson FC, Volkman BF, Ramirez-Alvarado M

Authors

Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amyloid
Humans
Hydrogen-Ion Concentration
Immunoglobulin Light Chains
Mutation
Nuclear Magnetic Resonance, Biomolecular
Protein Multimerization
Tyrosine
jenkins-FCD Prod-444 eb4ebd1a08581aba961d3befd3b851a3c3ec6b46