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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,23]]},"abstract":"<jats:p>H\/ACA small nucleolar ribonucleoproteins (H\/ACA snoRNPs) facilitate essential cellular processes such as RNA modification, folding, and stability. Here, we present multiple cryo-EM structures of endogenous insect H\/ACA snoRNPs containing two protomers assembled on a two-hairpin H\/ACA snoRNA. By characterizing key protein\u2013protein and protein\u2013RNA interactions, we reveal the coordination of pseudouridylation activity across the two protomers which explains the predominance of two-hairpin structures in eukaryotic H\/ACA snoRNAs. Moreover, we found that several mutations in H\/ACA proteins associated with dyskeratosis congenita (DC) directly impair pseudouridine formation suggesting how these mutations disrupt RNA modification and ribosome biogenesis in this disease. Additionally, we uncover coordinated structural changes between Nop10, Nhp2, and the N-terminal extensions of Cbf5 in the 3\u2032 protomer that resemble active and inactive conformations and may regulate H\/ACA snoRNP activity. In summary, this study provides detailed insight into the structure and function of RNA modification-competent H\/ACA snoRNPs, which play pivotal roles in cellular processes including ribosome biogenesis, rRNA folding, (m)RNA modification, and telomere maintenance.<\/jats:p>","DOI":"10.1073\/pnas.2514683122","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T16:04:20Z","timestamp":1766073860000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Interprotomer communication and functional asymmetry in H\/ACA snoRNPs"],"prefix":"10.1073","volume":"122","author":[{"given":"Hemendra Singh","family":"Panwar","sequence":"first","affiliation":[{"name":"Department of Structural Biology, Van Andel Institute","place":["Grand Rapids"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Vos","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Manitoba","place":["Winnipeg, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, Van Andel Institute","place":["Grand Rapids"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Josh","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Van Andel Institute","place":["Grand Rapids"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyoungjoo","family":"Lee","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Core, Van Andel Institute","place":["Grand Rapids"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan D.","family":"Sheldon","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Core, Van Andel Institute","place":["Grand Rapids"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0644-166X","authenticated-orcid":false,"given":"Evan J.","family":"Worden","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, Van Andel Institute","place":["Grand Rapids"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2744-7334","authenticated-orcid":false,"given":"Ute","family":"Kothe","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Manitoba","place":["Winnipeg, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00412-005-0333-9"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","unstructured":"P. Fischer . H\/ACA snR30 snoRNP guides independent 18S rRNA subdomain formation. Nat Commun 16 4720 (2025).","DOI":"10.1038\/s41467-025-59656-8"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9102195"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2022.2078092"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.1.567"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.3.598"},{"key":"e_1_3_4_7_2","first-page":"1833","article-title":"The snoRNA domain of vertebrate telomerase RNA functions to localize the RNA within the nucleus","volume":"7","author":"Lukowiak A. A.","year":"2001","unstructured":"A. A. Lukowiak, A. Narayanan, Z. H. Li, R. M. Terns, M. P. Terns, The snoRNA domain of vertebrate telomerase RNA functions to localize the RNA within the nucleus. 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