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The lens crystallin protein family correctly orders the formation of homo\u2010 or hetero\u2010oligomers in lens fiber cells. Because lens fiber cells do not divide, covalent post\u2010translational modifications, such as isomerization of aspartate residues, accumulate with aging. Although many isomerization sites of \u03b1A\u2010crystallin have been reported, their structural and functional contributions have never been identified. In this study, \u03b1A\u2010crystallin was extracted from aged human lens and separated into each oligomeric state by size exclusion chromatography and electrophoresis. The novel combination methodology of in\u2010solution\/gel tryptic digestion with liquid chromatography equipped with mass spectrometry (<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>) was used to evaluate the isomerization of Asp 58. The contributions of isomerization to assembly, solubility, and chaperone functions of \u03b1A\u2010crystallin were estimated using a series of mutations of Asp 58 in \u03b1A\u2010crystallin. The results indicated that the isomerization of Asp 58 depended on the oligomer size and age of the lens. The substitution of Asp 58 for hydrophobic residues increased \u03b1A\u2010crystallin oligomer size and decreased solubility. All substitutions decreased the chaperone function of \u03b1A\u2010crystallin for aggregates of bovine \u03b2L\u2010crystallin and alcohol dehydrogenase. The data indicated that Asp 58 in \u03b1A\u2010crystallin was critical for intermolecular interactions in the lens. Our results also suggested that <jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>\u2010based isomerization analyses of in\u2010gel\u2010digested products could be useful for investigating the isomerization of Asp residues in oligomeric states. This method could also be used to analyze <jats:sc>d<\/jats:sc>\/<jats:sc>l<\/jats:sc> ratios of amino acid residues in soluble protein aggregates.<\/jats:p>","DOI":"10.1111\/febs.14475","type":"journal-article","created":{"date-parts":[[2018,4,20]],"date-time":"2018-04-20T13:49:38Z","timestamp":1524232178000},"page":"2263-2277","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Asp 58 modulates lens \u03b1A\u2010crystallin oligomer formation and chaperone function"],"prefix":"10.1111","volume":"285","author":[{"given":"Takumi","family":"Takata","sequence":"first","affiliation":[{"name":"Research Reactor Institute Kyoto University Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tooru","family":"Nakamura\u2010Hirota","sequence":"additional","affiliation":[{"name":"ShinSei Lab Co., Ltd. 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