{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:38:09Z","timestamp":1790818689638,"version":"4.1.0"},"reference-count":61,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T00:00:00Z","timestamp":1607904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R35GM127073"],"award-info":[{"award-number":["5R35GM127073"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    The integral membrane zinc metalloprotease ZMPSTE24 plays a key role in the proteolytic processing of farnesylated prelamin A, the precursor of the nuclear scaffold protein lamin A. Failure of this processing step results in the accumulation of permanently farnesylated forms of prelamin A which cause the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS), as well as related progeroid disorders, and may also play a role in physiological aging. ZMPSTE24 is an intriguing and unusual protease because its active site is located inside of a closed intramembrane chamber formed by seven transmembrane spans with side portals in the chamber permitting substrate entry. The specific features of prelamin A that make it the sole known substrate for ZMPSTE24 in mammalian cells are not well-defined. At the outset of this work it was known that farnesylation is essential for prelamin A cleavage\n                    <jats:italic>in vivo<\/jats:italic>\n                    and that the C-terminal region of prelamin A (41 amino acids) is sufficient for recognition and processing. Here we investigated additional features of prelamin A that are required for cleavage by ZMPSTE24 using a well-established humanized yeast system. We analyzed the 14-residue C-terminal region of prelamin A that lies between the ZMPSTE24 cleavage site and the farnesylated cysteine, as well 23-residue region N-terminal to the cleavage site, by generating a series of alanine substitutions, alanine additions, and deletions in prelamin A. Surprisingly, we found that there is considerable flexibility in specific requirements for the length and composition of these regions. We discuss how this flexibility can be reconciled with ZMPSTE24\u2019s selectivity for prelamin A.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0239269","type":"journal-article","created":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T13:37:40Z","timestamp":1607953060000},"page":"e0239269","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Defining substrate requirements for cleavage of farnesylated prelamin A by the integral membrane zinc metalloprotease ZMPSTE24"],"prefix":"10.1371","volume":"15","author":[{"given":"Kaitlin M.","family":"Wood","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1980-0123","authenticated-orcid":true,"given":"Eric D.","family":"Spear","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6541-6072","authenticated-orcid":true,"given":"Otto W.","family":"Mossberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0243-2395","authenticated-orcid":true,"given":"Kamsi O.","family":"Odinammadu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5851-5021","authenticated-orcid":true,"given":"Susan","family":"Michaelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,14]]},"reference":[{"issue":"45","key":"pone.0239269.ref001","doi-asserted-by":"crossref","first-page":"30433","DOI":"10.1074\/jbc.R800035200","article-title":"Proteases: multifunctional enzymes in life and disease","volume":"283","author":"C Lopez-Otin","year":"2008","journal-title":"J Biol Chem"},{"issue":"7","key":"pone.0239269.ref002","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1038\/emboj.2012.42","article-title":"Protease signalling: the cutting edge","volume":"31","author":"B Turk","year":"2012","journal-title":"EMBO J"},{"issue":"8","key":"pone.0239269.ref003","doi-asserted-by":"crossref","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":"J Barrowman","year":"2009","journal-title":"Biol Chem"},{"key":"pone.0239269.ref004","article-title":"Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology","author":"BR Goblirsch","year":"2020","journal-title":"J Mol Biol"},{"issue":"6127","key":"pone.0239269.ref005","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1126\/science.1236764","article-title":"Biochemistry. A protease for the ages","volume":"339","author":"S Michaelis","year":"2013","journal-title":"Science"},{"issue":"20","key":"pone.0239269.ref006","doi-asserted-by":"crossref","first-page":"13049","DOI":"10.1073\/pnas.192460799","article-title":"Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect","volume":"99","author":"MO Bergo","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pone.0239269.ref007","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/ng871","article-title":"Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice","volume":"31","author":"AM Pendas","year":"2002","journal-title":"Nat Genet"},{"issue":"16","key":"pone.0239269.ref008","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1093\/hmg\/ddg213","article-title":"Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral 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Eriksson","year":"2003","journal-title":"Nature"},{"issue":"5","key":"pone.0239269.ref012","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1111\/j.0022-202X.2005.23846.x","article-title":"Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive dermopathy","volume":"125","author":"CL Moulson","year":"2005","journal-title":"J Invest Dermatol"},{"issue":"11","key":"pone.0239269.ref013","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1093\/hmg\/ddi159","article-title":"Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors","volume":"14","author":"CL Navarro","year":"2005","journal-title":"Hum Mol Genet"},{"issue":"8","key":"pone.0239269.ref014","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/ejhg.2013.258","article-title":"New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation 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