Structural and functional consequences of age-related isomerization in α-crystallins

The Journal of Biological Chemistry
Yana A LyonRyan R Julian

Abstract

Long-lived proteins are subject to spontaneous degradation and may accumulate a range of modifications over time, including subtle alterations such as side-chain isomerization. Recently, tandem MS has enabled identification and characterization of such peptide isomers, including those differing only in chirality. However, the structural and functional consequences of these perturbations remain largely unexplored. Here, we examined the impact of isomerization of aspartic acid or epimerization of serine at four sites mapping to crucial oligomeric interfaces in human αA- and αB-crystallin, the most abundant chaperone proteins in the eye lens. To characterize the effect of isomerization on quaternary assembly, we utilized synthetic peptide mimics, enzyme assays, molecular dynamics calculations, and native MS experiments. The oligomerization of recombinant forms of αA- and αB-crystallin that mimic isomerized residues deviated from native behavior in all cases. Isomerization also perturbs recognition of peptide substrates, either enhancing or inhibiting kinase activity. Specifically, epimerization of serine (αASer-162) dramatically weakened inter-subunit binding. Furthermore, phosphorylation of αBSer-59, known to play an important re...Continue Reading

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Citations

May 12, 2019·The Journal of Biological Chemistry·Alex J Guseman, Angela M Gronenborn
Jun 23, 2019·The Journal of Biological Chemistry·Allen Taylor
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Sep 10, 2019·Analytical Chemistry·Dylan L RiggsRyan R Julian
Feb 4, 2022·Journal of the American Society for Mass Spectrometry·Jacob W SilzelRyan R Julian

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Methods Mentioned

BETA
NMR
light-scattering

Software Mentioned

Antechamber
GERAIPV
NAMD
Schrödinger Maestro
UniDec

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