ArticleProtein science : a publication of the Protein Society2017
Human CaaX protease ZMPSTE24 expressed in yeast: Structure and inhibition by HIV protease inhibitors.
Article in Protein science : a publication of the Protein Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- The zinc metalloprotease ZMPSTE24 binds a distinct topological isoform of the tail-anchored protein IFITM3.The Journal of biological chemistry · 2026Article
- The zinc metalloprotease ZMPSTE24 binds a distinct topological isoform of the tail-anchored protein IFITM3.bioRxiv : the preprint server for biology · 2026Article
- Effects of Ritonavir, Lopinavir, and Alcohol on ABC Transporters and Secretion of Bile Acid and Bilirubin in Senescent Hepatocytes.International journal of molecular sciences · 2026Article
- Structure Bioinformatics of Six Human Integral Transmembrane Enzymes and their AlphaFold3 Predicted Water-Soluble QTY Analogs: Insights into FACE1 and STEA4 Binding Mechanisms.Pharmaceutical research · 2025Article
- Prelamin A and ZMPSTE24 in premature and physiological aging.Nucleus (Austin, Tex.) · 2023Review
- Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors.International journal of molecular sciences · 2023Review
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- OMA1-An integral membrane protease?Biochimica et biophysica acta. Proteins and proteomics · 2021Review
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- Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology.Journal of molecular biology · 2020Review
- Ritonavir and Lopinavir Suppress RCE1 and CAAX Rab Proteins Sensitizing the Liver to Organelle Stress and Injury.Hepatology communications · 2020Article
- The tripartite architecture of the eukaryotic integral membrane protein zinc metalloprotease Ste24.Proteins · 2020Article
- Defining substrate requirements for cleavage of farnesylated prelamin A by the integral membrane zinc metalloprotease ZMPSTE24.PloS one · 2020Article
- A humanized yeast system to analyze cleavage of prelamin A by ZMPSTE24.Methods (San Diego, Calif.) · 2019Review
- Membrane properties that shape the evolution of membrane enzymes.Current opinion in structural biology · 2018Review
- Phosphoramidon inhibits the integral membrane protein zinc metalloprotease ZMPSTE24.Acta crystallographica. Section D, Structural biology · 2018Article
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- Site specificity determinants for prelamin A cleavage by the zinc metalloprotease ZMPSTE24.The Journal of biological chemistryArticle
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The function and localization of proteins and peptides containing C-terminal "CaaX" (Cys-aliphatic-aliphatic-anything) sequence motifs are modulated by post-translational attachment of isoprenyl groups to the cysteine sulfhydryl, followed by proteolytic cleavage of the aaX amino acids. The zinc metalloprotease ZMPSTE24 is one of two enzymes known to catalyze this cleavage. The only identified target of mammalian ZMPSTE24 is prelamin A, the precursor to the nuclear scaffold protein lamin A. ZMPSTE24 also cleaves prelamin A at a second site 15 residues upstream from the CaaX site. Mutations in ZMPSTE24 result in premature-aging diseases and inhibition of ZMPSTE24 activity has been reported to be an off-target effect of HIV protease inhibitors. We report here the expression (in yeast), purification, and crystallization of human ZMPSTE24 allowing determination of the structure to 2.0 Å resolution. Compared to previous lower resolution structures, the enhanced resolution provides: (1) a detailed view of the active site of ZMPSTE24, including water coordinating the catalytic zinc; (2) enhanced visualization of fenestrations providing access from the exterior to the interior cavity of the protein; (3) a view of the C-terminus extending away from the main body of the protein; (4) localization of ordered lipid and detergent molecules at internal and external surfaces and also projecting through fenestrations; (5) identification of water molecules associated with the surface of the internal cavity. We also used a fluorogenic assay of the activity of purified ZMPSTE24 to demonstrate that HIV protease inhibitors directly inhibit the human enzyme in a manner indicative of a competitive mechanism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.