Yana A. Lyon
Structural and functional consequences of age-related isomerization in α-crystallins
Lyon, Yana A.; Collier, Miranda P.; Riggs, Dylan L.; Degiacomi, Matteo T.; Benesch, Justin L.P.; Julian, Ryan R.
Authors
Miranda P. Collier
Dylan L. Riggs
Matteo Degiacomi matteo.t.degiacomi@durham.ac.uk
Part Time Teacher
Justin L.P. Benesch
Ryan 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 regulatory role in oligomerization, was severely inhibited by serine epimerization and altered by isomerization of nearby αBAsp-62. Similarly, isomerization of αBAsp-109 disrupted a vital salt bridge with αBArg-120, a contact that when broken has previously been shown to yield aberrant oligomerization and aggregation in several disease-associated variants. Our results illustrate how isomerization of amino acid residues, which may seem to be only a minor structural perturbation, can disrupt native structural interactions with profound consequences for protein assembly and activity.
Citation
Lyon, Y. A., Collier, M. P., Riggs, D. L., Degiacomi, M. T., Benesch, J. L., & Julian, R. R. (2019). Structural and functional consequences of age-related isomerization in α-crystallins. Journal of Biological Chemistry, 294(19), 7546-7555. https://doi.org/10.1074/jbc.ra118.007052
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 25, 2019 |
Online Publication Date | Feb 25, 2019 |
Publication Date | May 10, 2019 |
Deposit Date | Apr 1, 2019 |
Publicly Available Date | May 21, 2019 |
Journal | Journal of Biological Chemistry |
Print ISSN | 0021-9258 |
Electronic ISSN | 1083-351X |
Publisher | American Society for Biochemistry and Molecular Biology |
Peer Reviewed | Peer Reviewed |
Volume | 294 |
Issue | 19 |
Article Number | 7546 |
Pages | 7546-7555 |
DOI | https://doi.org/10.1074/jbc.ra118.007052 |
Public URL | https://durham-repository.worktribe.com/output/1299577 |
Files
Published Journal Article
(1.9 Mb)
PDF
Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
Copyright Statement
This article is available open access under the terms of the Creative Commons CC-BY license.
You might also like
Course Materials for an Introduction to Data-Driven Chemistry
(2023)
Journal Article
Identification of Graphene Dispersion Agents through Molecular Fingerprints
(2022)
Journal Article
Allophycocyanin A is a carbon dioxide receptor in the cyanobacterial phycobilisome
(2022)
Journal Article
Complementing machine learning‐based structure predictions with native mass spectrometry
(2022)
Journal Article
Downloadable Citations
About Durham Research Online (DRO)
Administrator e-mail: dro.admin@durham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search