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| | <StructureSection load='5syt' size='340' side='right'caption='[[5syt]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='5syt' size='340' side='right'caption='[[5syt]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5syt]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SYT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5SYT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5syt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SYT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SYT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C8E:(HYDROXYETHYLOXY)TRI(ETHYLOXY)OCTANE'>C8E</scene>, <scene name='pdbligand=CXE:PENTAETHYLENE+GLYCOL+MONODECYL+ETHER'>CXE</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PC1:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PC1</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4aw6|4aw6]], [[2ypt|2ypt]], [[4il3|4il3]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C8E:(HYDROXYETHYLOXY)TRI(ETHYLOXY)OCTANE'>C8E</scene>, <scene name='pdbligand=CXE:PENTAETHYLENE+GLYCOL+MONODECYL+ETHER'>CXE</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PC1:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PC1</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ZMPSTE24, FACE1, STE24 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5syt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5syt OCA], [https://pdbe.org/5syt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5syt RCSB], [https://www.ebi.ac.uk/pdbsum/5syt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5syt ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ste24_endopeptidase Ste24 endopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.84 3.4.24.84] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5syt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5syt OCA], [http://pdbe.org/5syt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5syt RCSB], [http://www.ebi.ac.uk/pdbsum/5syt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5syt ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/FACE1_HUMAN FACE1_HUMAN]] Mandibuloacral dysplasia with type B lipodystrophy;Hutchinson-Gilford progeria syndrome;Lethal restrictive dermopathy. Mandibuloacral dysplasia with type B lipodystrophy (MADB) [MIM:[http://omim.org/entry/608612 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.<ref>PMID:12913070</ref> <ref>PMID:17152860</ref> <ref>PMID:18435794</ref> <ref>PMID:20814950</ref> Lethal tight skin contracture syndrome (LTSCS) [MIM:[http://omim.org/entry/275210 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.<ref>PMID:15317753</ref> | + | [https://www.uniprot.org/uniprot/FACE1_HUMAN FACE1_HUMAN] Mandibuloacral dysplasia with type B lipodystrophy;Hutchinson-Gilford progeria syndrome;Lethal restrictive dermopathy. Mandibuloacral dysplasia with type B lipodystrophy (MADB) [MIM:[https://omim.org/entry/608612 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.<ref>PMID:12913070</ref> <ref>PMID:17152860</ref> <ref>PMID:18435794</ref> <ref>PMID:20814950</ref> Lethal tight skin contracture syndrome (LTSCS) [MIM:[https://omim.org/entry/275210 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.<ref>PMID:15317753</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FACE1_HUMAN FACE1_HUMAN]] Proteolytically removes the C-terminal three residues of farnesylated proteins. Acts on lamin A/C. | + | [https://www.uniprot.org/uniprot/FACE1_HUMAN FACE1_HUMAN] Proteolytically removes the C-terminal three residues of farnesylated proteins. Acts on lamin A/C. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ste24 endopeptidase]]
| + | [[Category: Clark K]] |
| - | [[Category: Clark, K]] | + | [[Category: Dumont ME]] |
| - | [[Category: Dumont, M E]] | + | [[Category: Fedoriw N]] |
| - | [[Category: Fedoriw, N]] | + | [[Category: Jenkins JL]] |
| - | [[Category: Jenkins, J L]] | + | |
| - | [[Category: MPSBC, Membrane Protein Structural Biology Consortium]]
| + | |
| - | [[Category: Caax protease]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Isoprenylation]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Membrane protein structural biology consortium]]
| + | |
| - | [[Category: Mpsbc]]
| + | |
| - | [[Category: PSI, Protein structure initiative]]
| + | |
| - | [[Category: Ste24]]
| + | |
| - | [[Category: Structural genomic]]
| + | |
| - | [[Category: Zinc metalloprotease]]
| + | |
| Structural highlights
5syt is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2Å |
| Ligands: | , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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 PubMed
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, 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
- ↑ Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet. 2003 Aug 15;12(16):1995-2001. PMID:12913070
- ↑ Agarwal AK, Zhou XJ, Hall RK, Nicholls K, Bankier A, Van Esch H, Fryns JP, Garg A. Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency. J Investig Med. 2006 May;54(4):208-13. PMID:17152860
- ↑ Miyoshi Y, Akagi M, Agarwal AK, Namba N, Kato-Nishimura K, Mohri I, Yamagata M, Nakajima S, Mushiake S, Shima M, Auchus RJ, Taniike M, Garg A, Ozono K. Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings. Clin Genet. 2008 Jun;73(6):535-44. doi: 10.1111/j.1399-0004.2008.00992.x. Epub, 2008 Apr 22. PMID:18435794 doi:10.1111/j.1399-0004.2008.00992.x
- ↑ Ahmad Z, Zackai E, Medne L, Garg A. Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24. Am J Med Genet A. 2010 Nov;152A(11):2703-10. doi: 10.1002/ajmg.a.33664. PMID:20814950 doi:10.1002/ajmg.a.33664
- ↑ Navarro CL, De Sandre-Giovannoli A, Bernard R, Boccaccio I, Boyer A, Genevieve D, Hadj-Rabia S, Gaudy-Marqueste C, Smitt HS, Vabres P, Faivre L, Verloes A, Van Essen T, Flori E, Hennekam R, Beemer FA, Laurent N, Le Merrer M, Cau P, Levy N. Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet. 2004 Oct 15;13(20):2493-503. Epub 2004 Aug 18. PMID:15317753 doi:10.1093/hmg/ddh265
- ↑ Clark KM, Jenkins JL, Fedoriw N, Dumont ME. Human CaaX Protease ZMPSTE24 Expressed in Yeast: Structure and Inhibition by HIV Protease Inhibitors. Protein Sci. 2016 Oct 24. doi: 10.1002/pro.3074. PMID:27774687 doi:http://dx.doi.org/10.1002/pro.3074
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