5syt | pdb_00005syt
Crystal Structure of ZMPSTE24
Structural highlights
Disease[FACE1_HUMAN] Mandibuloacral dysplasia with type B lipodystrophy;Hutchinson-Gilford progeria syndrome;Lethal restrictive dermopathy. Mandibuloacral dysplasia with type B lipodystrophy (MADB) [MIM:608612]: A disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of the cranial suture, joint contractures, and generalized lipodystrophy with loss of subcutaneous fat from the extremities, face, neck and trunk. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] Lethal tight skin contracture syndrome (LTSCS) [MIM:275210]: Rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. Note=The disease is caused by mutations affecting the gene represented in this entry.[5] Function[FACE1_HUMAN] Proteolytically removes the C-terminal three residues of farnesylated proteins. Acts on lamin A/C. Publication Abstract from PubMedThe 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, purification, and crystallization of human ZMPSTE24 allowing determination of the structure to 2.0 A 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 internal surface 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. This article is protected by copyright. All rights reserved. Human CaaX Protease ZMPSTE24 Expressed in Yeast: Structure and Inhibition by HIV Protease Inhibitors.,Clark KM, Jenkins JL, Fedoriw N, Dumont ME Protein Sci. 2016 Oct 24. doi: 10.1002/pro.3074. PMID:27774687[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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