{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:15:20Z","timestamp":1790680520167,"version":"4.1.0"},"reference-count":84,"publisher":"The Company of Biologists","issue":"7","license":[{"start":{"date-parts":[[2020,9,5]],"date-time":"2020-09-05T00:00:00Z","timestamp":1599264000000},"content-version":"vor","delay-in-days":797,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM041223"],"award-info":[{"award-number":["R01 GM041223"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM106082"],"award-info":[{"award-number":["R01 GM106082"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L017458\/1"],"award-info":[{"award-number":["MR\/L017458\/1"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023921","name":"Structural Genomics Consortium","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100023921","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,7,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The human zinc metalloprotease ZMPSTE24 is an integral membrane protein crucial for the final step in the biogenesis of the nuclear scaffold protein lamin A, encoded by LMNA. After farnesylation and carboxyl methylation of its C-terminal CAAX motif, the lamin A precursor (prelamin A) undergoes proteolytic removal of its modified C-terminal 15 amino acids by ZMPSTE24. Mutations in LMNA or ZMPSTE24 that impede this prelamin A cleavage step cause the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS), and the related progeroid disorders mandibuloacral dysplasia type B (MAD-B) and restrictive dermopathy (RD). Here, we report the development of a \u2018humanized yeast system\u2019 to assay ZMPSTE24-dependent cleavage of prelamin A and examine the eight known disease-associated ZMPSTE24 missense mutations. All mutations show diminished prelamin A processing and fall into three classes, with defects in activity, protein stability or both. Notably, some ZMPSTE24 mutants can be rescued by deleting the E3 ubiquitin ligase Doa10, involved in endoplasmic reticulum (ER)-associated degradation of misfolded membrane proteins, or by treatment with the proteasome inhibitor bortezomib. This finding may have important therapeutic implications for some patients. We also show that ZMPSTE24-mediated prelamin A cleavage can be uncoupled from the recently discovered role of ZMPSTE24 in clearance of ER membrane translocon-clogged substrates. Together with the crystal structure of ZMPSTE24, this humanized yeast system can guide structure-function studies to uncover mechanisms of prelamin A cleavage, translocon unclogging, and membrane protein folding and stability.<\/jats:p>","DOI":"10.1242\/dmm.033670","type":"journal-article","created":{"date-parts":[[2018,5,24]],"date-time":"2018-05-24T07:00:07Z","timestamp":1527145207000},"source":"Crossref","is-referenced-by-count":40,"title":["<i>ZMPSTE24<\/i>\n                    missense mutations that cause progeroid diseases decrease prelamin A cleavage activity and\/or protein stability"],"prefix":"10.1242","volume":"11","author":[{"given":"Eric D.","family":"Spear","sequence":"first","affiliation":[{"name":"The Johns Hopkins School of Medicine 1 Department of Cell Biology , , Baltimore, MD 21205 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erh-Ting","family":"Hsu","sequence":"additional","affiliation":[{"name":"Purdue University 2 Department of Chemistry , , West Lafayette, IN 47907 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laiyin","family":"Nie","sequence":"additional","affiliation":[{"name":"Structural Genomics Consortium, University of Oxford 3 , Oxford OX3 7DQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth P.","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Structural Genomics Consortium, University of Oxford 3 , Oxford OX3 7DQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Hrycyna","sequence":"additional","affiliation":[{"name":"Purdue University 2 Department of Chemistry , , West Lafayette, IN 47907 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5912-8744","authenticated-orcid":false,"given":"Susan","family":"Michaelis","sequence":"additional","affiliation":[{"name":"The Johns Hopkins School of Medicine 1 Department of Cell Biology , , Baltimore, MD 21205 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2018,7,13]]},"reference":[{"key":"2024061303460235400_DMM033670C1","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1093\/hmg\/ddg213","article-title":"Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia","volume":"12","author":"Agarwal","year":"2003","journal-title":"Hum. 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Mol. Case Stud."},{"key":"2024061303460235400_DMM033670C5","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1111\/joim.12314","article-title":"Novel personalized therapies for cystic fibrosis: treating the basic defect in all patients","volume":"277","author":"Amaral","year":"2015","journal-title":"J. Intern. Med."},{"key":"2024061303460235400_DMM033670C6","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.cell.2015.11.053","article-title":"The protease Ste24 clears clogged translocons","volume":"164","author":"Ast","year":"2016","journal-title":"Cell"},{"key":"2024061303460235400_DMM033670C7","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1515\/BC.2009.080","article-title":"ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders","volume":"390","author":"Barrowman","year":"2009","journal-title":"Biol. Chem."},{"key":"2024061303460235400_DMM033670C8","first-page":"13","article-title":"CAAX processing and yeast a-factor biogenesis","volume":"30","author":"Barrowman","year":"2011","journal-title":"Enzymes, Vol 30: Protein Prenylation, Pt B"},{"key":"2024061303460235400_DMM033670C9","doi-asserted-by":"publisher","first-page":"5398","DOI":"10.1091\/mbc.e08-07-0704","article-title":"Analysis of prelamin A biogenesis reveals the nucleus to be a CaaX processing compartment","volume":"19","author":"Barrowman","year":"2008","journal-title":"Mol. Biol. 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