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Recently, there has been excitement about the promise of advances in protein structure modeling to generate hypotheses about sequence-structure-function relationships based on successes with controlled benchmarks. Here, we leverage structural similarity to identify rapidly evolving proteasome assembly chaperones and characterize their function in the emerging fungal pathogen\n                  <jats:italic>Candida auris<\/jats:italic>\n                  . Despite the large sequence divergence, we demonstrate conservation of structure and function across hundreds of millions of years of evolution, representing a case of rapid neutral evolution. Using the functional constraints on structure from these naturally evolved sequences, we prospectively designed\n                  <jats:italic>de novo<\/jats:italic>\n                  chaperones and demonstrate that these artificial proteins can rescue complex biological processes in the context of the whole cell.\n                <\/jats:p>","DOI":"10.1101\/2025.05.14.654010","type":"posted-content","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T14:50:16Z","timestamp":1747320616000},"source":"Crossref","is-referenced-by-count":0,"title":["Deep homology and design of proteasome chaperone proteins in\n                  <i>Candida auris<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0501-4615","authenticated-orcid":false,"given":"Jackson R.","family":"Rapala","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School; Ann Arbor MI 48019 USA."},{"name":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School; Ann Arbor MI 48019 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9186-1978","authenticated-orcid":false,"given":"Mohammad","family":"Siddiq","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, University of Michigan; Ann Arbor MI 48019 USA."},{"name":"Department of Molecular, Cellular, and Developmental Biology, University of Michigan; Ann Arbor MI 48019 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-0048","authenticated-orcid":false,"given":"Patricia J.","family":"Wittkopp","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, University of Michigan; Ann Arbor MI 48019 USA."},{"name":"Department of Molecular, Cellular, and Developmental Biology, University of Michigan; Ann Arbor MI 48019 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"O\u2019Meara","sequence":"additional","affiliation":[{"name":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School; Ann Arbor MI 48019 USA."},{"name":"Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8901-0154","authenticated-orcid":false,"given":"Teresa R.","family":"O\u2019Meara","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan Medical School; Ann Arbor MI 48019 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041122032788000_2025.05.14.654010v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/12.2.85"},{"key":"2026041122032788000_2025.05.14.654010v1.2","first-page":"1742","article-title":"The structure of genotype-phenotype maps makes fitness landscapes navigable. Nat","volume":"6","year":"2022","journal-title":"Ecol. 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