{ "abstract": "Archaea represent one of the three domains of cellular life and yet account for fewer than 1% of experimentally determined protein structures, leaving the extent of their structural novelty unknown. Here we present a systematic domain-level classification of 124,075 proteins from 65 archaeal classes spanning 21 phyla and all major lineages, using both AFDB and newly predicted AlphaFold3 structures classified against the Evolutionary Classification of protein Domains (ECOD). Archaeal proteins span 987 of the 2,457 ECOD X-groups defined across all cellular life, roughly 40% of known fold diversity captured within a single domain of life. Clustering by Foldseek recovered structural relationships for 63% of domains that are singletons by sequence comparison. To characterize the 21% of proteins lacking high-confidence classification, we applied successive filters for structure prediction confidence, protein length, and structural cluster context, reducing 8,452 domain-free proteins to a small number of well-folded structural orphans (less than 0.1% of the dataset). The unclassified fraction is dominated by sub-threshold matches (matches below the 0.85 DPAM confidence cutoff for high-confidence T-group assignment) to known folds (14% of all proteins) and low-confidence structure predictions (5%), not by novel structures. These results demonstrate that the protein fold repertoire at the single-domain level is broadly conserved across the deepest phylogenetic distances in cellular life, and that the gap between archaeal and well-characterized proteomes reflects classification sensitivity for divergent sequences rather than unexplored structural diversity. Author summary: Archaea are the least-studied of the three domains of life, yet they matter enormously: they flourish in extreme environments, drive global nutrient cycles, and are closely tied to the origin of eukaryotes, the group that includes our own cells. What most of their proteins do, and where those proteins came from, remains largely uncharted. Proteins are built from folded modules called domains. A domain’s three-dimensional structure is a lasting record of its evolutionary history, changing far more slowly than the gene sequence that encodes it. Using structures predicted by AlphaFold, we classified the domains in more than 120,000 proteins spanning the breadth of archaeal diversity and compared their folds with those of bacteria and eukaryotes. Archaea are not a hidden reservoir of novel structural designs: almost all of their folds are shared with the other domains of cellular life, and archaea occupy roughly 40% of known structural fold diversity. What distinguishes archaeal and eukaryotic cells is therefore not the invention of new folds, but new ways of combining and elaborating on an ancient shared repertoire.", "abstract_shown": true, "affiliations": [ "Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America", "Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America", "Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America", "Department of Computer Science, University of Central Florida, Orlando, Florida, United States of America", "Genomics & Bioinformatics Cluster, University of Central Florida, Orlando, Florida, United States of America", "Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 7, "authors": [ { "affs": [ 0 ], "name": "R. Dustin Schaeffer" }, { "affs": [ 1 ], "name": "Jimin Pei" }, { "affs": [ 2 ], "name": "Rui Guo" }, { "affs": [ 3 ], "name": "Jing Zhang" }, { "affs": [ 4 ], "name": "Kirill Medvedev" }, { "affs": [ 5 ], "name": "Qian Cong" }, { "name": "Nick Grishin" } ], "bibtex": "https://research.draconitic.com/paper/7qbbg7dt6cjt1.bib", "cited_by": 0, "doi": "10.1371/journal.pcbi.1014188", "fulltext_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014188", "id": "7qbbg7dt6cjt1", "issns": [ "1553-7358" ], "landing_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014188", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1312|Protein Structure and Dynamics" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Protein domains" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Protein structure" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Protein structure/Protein folding" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Protein structure/Protein structure databases" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Protein structure/Protein structure prediction" ], [ "plos", "/Biology and life sciences/Microbiology/Archaean biology" ], [ "plos", "/Biology and life sciences/Molecular biology/Macromolecular structure analysis/Protein structure" ], [ "plos", "/Biology and life sciences/Molecular biology/Macromolecular structure analysis/Protein structure/Protein folding" ], [ "plos", "/Biology and life sciences/Molecular biology/Macromolecular structure analysis/Protein structure/Protein structure databases" ], [ "plos", "/Biology and life sciences/Molecular biology/Macromolecular structure analysis/Protein structure/Protein structure prediction" ], [ "plos", "/Biology and life sciences/Organisms/Archaea" ], [ "plos", "/Biology and life sciences/Organisms/Eukaryota" ], [ "plos", "/Research and analysis methods/Database and informatics methods/Biological databases/Protein structure databases" ] ], "openalex": "W7213555759", "pdf_url": "https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1014188&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-18", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/7qbbg7dt6cjt1.ris", "sources": [ { "first_seen": "2026-10-30T12:17:49Z", "native_id": "10.1371/journal.pcbi.1014188", "source": "plos", "url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014188" } ], "subjects": [ { "field": "biochemistry", "origin": "plos:molecular biology", "subfield": "molecular-biology" } ], "title": "Domain classification of archaeal proteomes reveals conserved fold repertoire", "title_text": "Domain classification of archaeal proteomes reveals conserved fold repertoire", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:49Z", "url": "https://research.draconitic.com/paper/7qbbg7dt6cjt1", "venue": "PLOS Computational Biology", "versions": [] }