| Title: | The tripartite architecture of the eukaryotic integral membrane protein zinc metalloprotease Ste24 |
| Author(s): | Goblirsch BR; Pryor EE; Wiener MC; |
| Address: | "Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia" |
| ISSN/ISBN: | 1097-0134 (Electronic) 0887-3585 (Print) 0887-3585 (Linking) |
| Abstract: | "Ste24 enzymes, a family of eukaryotic integral membrane proteins, are zinc metalloproteases (ZMPs) originally characterized as 'CAAX proteases' targeting prenylated substrates, including a-factor mating pheromone in yeast and prelamin A in humans. 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 'alpha-barrel' structure consisting of seven transmembrane (TM) alpha-helices encircling a large intramembranous cavity (~14 000 A(3) ). The catalytic zinc, coordinated via a HExxH...E/H motif characteristic of gluzincin ZMPs, is positioned at one of the cavity's bases. The interrelationship between Ste24 as a gluzincin, a long-studied class of soluble ZMPs, and as a novel cavity-containing integral membrane protein protease has been minimally explored to date. Informed by homology to well-characterized 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-containing 'ZMP Core' module surrounded by a 'ZMP Accessory' module, both capped by a TM helical 'alpha-barrel' 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 alpha-barrel (7) modules. This Tripartite Architecture representation of Ste24 provides a unified image of this enzyme family" |
| Keywords: | "Amino Acid Sequence Bacillus/chemistry/enzymology Binding Sites Conserved Sequence Crystallography, X-Ray Geobacter/chemistry/enzymology Humans Membrane Proteins/*chemistry/genetics/metabolism Metalloendopeptidases/*chemistry/genetics/metabolism Models, M;" |
| Notes: | "MedlineGoblirsch, Brandon R Pryor, Edward E Jr Wiener, Michael C eng R01 GM108612/GM/NIGMS NIH HHS/ R56 AI141627/AI/NIAID NIH HHS/ R01GM108612/NH/NIH HHS/ R56AI141627/NH/NIH HHS/ Research Support, N.I.H., Extramural 2019/10/24 Proteins. 2020 Apr; 88(4):604-615. doi: 10.1002/prot.25841. Epub 2019 Nov 5" |
