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Recently, Ste24 was shown to also cleave nonprenylated substrates. Reduced activity of the human ortholog, HsSte24, is linked to multiple disease states (laminopathies), including progerias and lipid disorders. Ste24 possesses a unique \u201c\u03b1\u2010barrel\u201d structure consisting of seven transmembrane (TM) \u03b1\u2010helices encircling a large intramembranous cavity (~14\u2009000\u2009\u00c5<jats:sup>3<\/jats:sup>). The catalytic zinc, coordinated via a HExxH\u2026E\/H motif characteristic of gluzincin ZMPs, is positioned at one of the cavity's bases. The interrelationship between Ste24 as a gluzincin, a long\u2010studied class of soluble ZMPs, and as a novel cavity\u2010containing integral membrane protein protease has been minimally explored to date. Informed by homology to well\u2010characterized soluble, gluzincin ZMPs, we develop a model of Ste24 that provides a conceptual framework for this enzyme family, suitable for development and interpretation of structure\/function studies. The model consists of an interfacial, zinc\u2010containing \u201cZMP Core\u201d module surrounded by a \u201cZMP Accessory\u201d module, both capped by a TM helical \u201c\u03b1\u2010barrel\u201d module of as yet unknown function. Multiple sequence alignment of 58 Ste24 orthologs revealed 38 absolutely conserved residues, apportioned unequally among the ZMP Core (18), ZMP Accessory (13), and \u03b1\u2010barrel (7) modules. This Tripartite Architecture representation of Ste24 provides a unified image of this enzyme family.<\/jats:p>","DOI":"10.1002\/prot.25841","type":"journal-article","created":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T19:33:44Z","timestamp":1571859224000},"page":"604-615","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The tripartite architecture of the eukaryotic integral membrane protein zinc metalloprotease Ste24"],"prefix":"10.1002","volume":"88","author":[{"given":"Brandon R.","family":"Goblirsch","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics University of Virginia  Charlottesville Virginia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr","given":"Edward E.","family":"Pryor","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics University of Virginia  Charlottesville Virginia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4032-6622","authenticated-orcid":false,"given":"Michael C.","family":"Wiener","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics University of Virginia  Charlottesville 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