| Title: | Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology |
| Address: | "Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: mwiener@virginia.edu" |
| DOI: | 10.1016/j.jmb.2020.03.016 |
| ISSN/ISBN: | 1089-8638 (Electronic) 0022-2836 (Print) 0022-2836 (Linking) |
| Abstract: | "Ste24, an integral membrane protein zinc metalloprotease, is found in every kingdom of eukaryotes. It was discovered approximately 20 years ago by yeast genetic screens identifying it as a factor responsible for processing the yeast mating a-factor pheromone. In animals, Ste24 processes prelamin A, a component of the nuclear lamina; mutations in the human ortholog of Ste24 diminish its activity, giving rise to genetic diseases of accelerated aging (progerias). Additionally, lipodystrophy, acquired from the standard highly active antiretroviral therapy used to treat AIDS patients, likely results from off-target interactions of HIV (aspartyl) protease inhibitor drugs with Ste24. Ste24 possesses a novel 'alpha-barrel' structure, consisting of a ring of seven transmembrane alpha-helices enclosing a large (>12,000?ª+A(3)) interior volume that contains the active-site and substrate-binding region; this 'membrane-interior reaction chamber' is unprecedented in integral membrane protein structures. Additionally, the surface of the membrane-interior reaction chamber possesses a strikingly large negative electrostatic surface potential, adding additional 'functional mystery.' Recent publications implicate Ste24 as a key factor in several endoplasmic reticulum processes, including the unfolded protein response, a cellular stress response of the endoplasmic reticulum, and removal of misfolded proteins from the translocon. Ste24, with its provocative structure, enigmatic mechanism, and recently emergent new biological roles including 'translocon unclogger' and (non-enyzmatic) broad-spectrum viral restriction factor, presents far differently than before 2016, when it was viewed as a 'CAAX protease' responsible for cleavage of prenylated (farnesylated or geranylgeranylated) substrates. The emphasis of this review is on Ste24 of the 'Post-CAAX-Protease Era.'" |
| Keywords: | "Animals;Animals Binding Sites Catalytic Domain Humans Lipodystrophy/chemically induced/*genetics Membrane Proteins/*chemistry/genetics/*metabolism Metalloendopeptidases/*chemistry/genetics/*metabolism Models, Molecular Mutation Progeria/*genetics Protein Structur;" |
| Notes: | "MedlineGoblirsch, Brandon R Wiener, Michael C eng R01 GM108612/GM/NIGMS NIH HHS/ R56 AI141627/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Review Netherlands 2020/03/23 J Mol Biol. 2020 Aug 21; 432(18):5079-5090. doi: 10.1016/j.jmb.2020.03.016. Epub 2020 Mar 19" |
