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Post\u2010translational modifications impact solubility and stability of the structural and refractive \u03b2\u03b3\u2010crystallins, eventually leading to cataract. Such damaged proteins are kept in solution by the holdase chaperone \u03b1\u2010crystallins, maintaining lens transparency over decades despite the absence of protein turnover. It was previously found that a short peptide from human \u03b1A\u2010crystallin (mini\u2010\u03b1A\u2010crystallin [MAAC]) retains some chaperone activity, with hydrophobic interactions hypothesized to mediate chaperone\u2013client interactions; MAAC has been hypothesized to have \u03b2\u2010strand structure in solution, although its conformational ensemble under these conditions has not been well\u2010characterized. Here, we employ a combination of nuclear magnetic resonance (NMR), circular dichroism spectroscopy, dynamic light scattering, and molecular dynamics simulations to examine the behavior of MAAC in dilute solution and in combination with human \u03b3S\u2010crystallin. Structural ensembles of two alanine variants of MAAC (I4A and L6A) show that the variants lack well\u2010defined secondary structure, but have a preference for a bent conformation with some self\u2010interaction. A partial alanine scan indicates that several hydrophobic residues are important for peptide solubility, also modifying the peptide's conformational ensemble. Tests of wild\u2010type MAAC chaperone activity on thermally stressed \u03b3S\u2010crystallin show little interaction between MAAC and the client protein below its unfolding temperature. However, MAAC does inhibit large\u2010scale aggregation at the \u03b3S\u2010crystallin unfolding temperature. NMR measurements indicate only weak, transient interaction with the client protein during the intermediate aggregation phase, suggesting a sharp phase transition in the MAAC\u2013client system.<\/jats:p>","DOI":"10.1002\/pro.70199","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T05:35:09Z","timestamp":1750656909000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mini\u2010\u03b1A\u2010crystallin protects a client lens protein from catastrophic aggregation due to heat stress"],"prefix":"10.1002","volume":"34","author":[{"given":"Collin","family":"Sroge","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Biochemistry UC Irvine  Irvine California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaewon","family":"Suk","sequence":"additional","affiliation":[{"name":"Department of Chemistry UC Irvine  Irvine California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Chemistry UC Irvine  Irvine California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Sophia Teresa Lee","family":"Padilla","sequence":"additional","affiliation":[{"name":"Department of Chemistry UC Irvine  Irvine California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian F.","family":"Baca","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry UC Irvine  Irvine California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carter T.","family":"Butts","sequence":"additional","affiliation":[{"name":"Department of Sociology UC Irvine  Irvine California USA"},{"name":"Department of Statistics UC Irvine  Irvine California USA"},{"name":"Department of Computer Science UC Irvine  Irvine California USA"},{"name":"Department 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