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| - | [[Image:1r5l.jpg|left|200px]] | |
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| - | <!--
| + | ==Crystal Structure of Human Alpha-Tocopherol Transfer Protein Bound to its Ligand== |
| - | The line below this paragraph, containing "STRUCTURE_1r5l", creates the "Structure Box" on the page.
| + | <StructureSection load='1r5l' size='340' side='right'caption='[[1r5l]], [[Resolution|resolution]] 1.50Å' scene=''> |
| - | You may change the PDB parameter (which sets the PDB file loaded into the applet)
| + | == Structural highlights == |
| - | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[1r5l]] 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=1R5L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1R5L FirstGlance]. <br> |
| - | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5Å</td></tr> |
| - | -->
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=VIV:(2R)-2,5,7,8-TETRAMETHYL-2-[(4R,8R)-4,8,12-TRIMETHYLTRIDECYL]CHROMAN-6-OL'>VIV</scene></td></tr> |
| - | {{STRUCTURE_1r5l| PDB=1r5l | SCENE= }}
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1r5l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1r5l OCA], [https://pdbe.org/1r5l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1r5l RCSB], [https://www.ebi.ac.uk/pdbsum/1r5l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1r5l ProSAT]</span></td></tr> |
| - | | + | </table> |
| - | '''Crystal Structure of Human Alpha-Tocopherol Transfer Protein Bound to its Ligand'''
| + | == Disease == |
| - | | + | [https://www.uniprot.org/uniprot/TTPA_HUMAN TTPA_HUMAN] Defects in TTPA are the cause of ataxia with isolated vitamin E deficiency (AVED) [MIM:[https://omim.org/entry/277460 277460]. AVED is an autosomal recessive disease characterized by spinocerebellar degeneration. It causes ataxia and peripheral neuropathy that resembles Friedreich ataxia. AVED patients have markedly reduced plasma levels of vitamin E.<ref>PMID:8602747</ref> <ref>PMID:9463307</ref> <ref>PMID:7719340</ref> <ref>PMID:7566022</ref> <ref>PMID:15065857</ref> <ref>PMID:15300460</ref> |
| - | | + | == Function == |
| - | ==Overview== | + | [https://www.uniprot.org/uniprot/TTPA_HUMAN TTPA_HUMAN] Binds alpha-tocopherol and enhances its transfer between separate membranes. |
| - | Human alpha-tocopherol (alpha-T) transfer protein (ATTP) plays a central role in vitamin E homeostasis, preventing degradation of alpha-T by routing this lipophilic molecule for secretion by hepatocytes. Mutations in the gene encoding ATTP have been shown to cause a severe deficiency in alpha-T, which results in a progressive neurodegenerative spinocerebellar ataxia, known as ataxia with vitamin E deficiency (AVED). We have determined the high-resolution crystal structure of human ATTP with (2R,4'R,8'R)-alpha-T in the binding pocket. Surprisingly, the ligand is sequestered deep in the hydrophobic core of the protein, implicating a large structural rearrangement for the entry and release of alpha-T. A comparison to the structure of a related protein, Sec14p, crystallized without a bona fide ligand, shows a possibly relevant open conformation for this family of proteins. Furthermore, of the known mutations that cause AVED, one mutation, L183P, is located directly in the binding pocket. Finally, three mutations associated with AVED involve arginine residues that are grouped together on the surface of ATTP. We propose that this positively charged surface may serve to orient an interacting protein, which might function to regulate the release of alpha-T through an induced change in conformation of ATTP.
| + | == Evolutionary Conservation == |
| - | | + | [[Image:Consurf_key_small.gif|200px|right]] |
| - | ==About this Structure== | + | Check<jmol> |
| - | 1R5L is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1R5L OCA].
| + | <jmolCheckbox> |
| - | | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r5/1r5l_consurf.spt"</scriptWhenChecked> |
| - | ==Reference== | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| - | Crystal structure of human alpha-tocopherol transfer protein bound to its ligand: implications for ataxia with vitamin E deficiency., Min KC, Kovall RA, Hendrickson WA, Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14713-8. Epub 2003 Dec 1. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14657365 14657365]
| + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1r5l ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Hendrickson, W A.]] | + | [[Category: Hendrickson WA]] |
| - | [[Category: Kovall, R A.]] | + | [[Category: Kovall RA]] |
| - | [[Category: Min, K C.]] | + | [[Category: Min KC]] |
| - | [[Category: Ataxia with vitamin e deficiency]]
| + | |
| - | [[Category: Attp]]
| + | |
| - | [[Category: Tocopherol]]
| + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:06:37 2008''
| + | |
| Structural highlights
Disease
TTPA_HUMAN Defects in TTPA are the cause of ataxia with isolated vitamin E deficiency (AVED) [MIM:277460. AVED is an autosomal recessive disease characterized by spinocerebellar degeneration. It causes ataxia and peripheral neuropathy that resembles Friedreich ataxia. AVED patients have markedly reduced plasma levels of vitamin E.[1] [2] [3] [4] [5] [6]
Function
TTPA_HUMAN Binds alpha-tocopherol and enhances its transfer between separate membranes.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
References
- ↑ Hentati A, Deng HX, Hung WY, Nayer M, Ahmed MS, He X, Tim R, Stumpf DA, Siddique T, Ahmed. Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Ann Neurol. 1996 Mar;39(3):295-300. PMID:8602747 doi:http://dx.doi.org/10.1002/ana.410390305
- ↑ Cavalier L, Ouahchi K, Kayden HJ, Di Donato S, Reutenauer L, Mandel JL, Koenig M. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet. 1998 Feb;62(2):301-10. PMID:9463307 doi:S0002-9297(07)63495-8
- ↑ Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, Arai H, Inoue K, Mandel JL, Koenig M. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet. 1995 Feb;9(2):141-5. PMID:7719340 doi:http://dx.doi.org/10.1038/ng0295-141
- ↑ Gotoda T, Arita M, Arai H, Inoue K, Yokota T, Fukuo Y, Yazaki Y, Yamada N. Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein. N Engl J Med. 1995 Nov 16;333(20):1313-8. PMID:7566022
- ↑ Morley S, Panagabko C, Shineman D, Mani B, Stocker A, Atkinson J, Manor D. Molecular determinants of heritable vitamin E deficiency. Biochemistry. 2004 Apr 13;43(14):4143-9. PMID:15065857 doi:10.1021/bi0363073
- ↑ Mariotti C, Gellera C, Rimoldi M, Mineri R, Uziel G, Zorzi G, Pareyson D, Piccolo G, Gambi D, Piacentini S, Squitieri F, Capra R, Castellotti B, Di Donato S. Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci. 2004 Jul;25(3):130-7. PMID:15300460 doi:10.1007/s10072-004-0246-z
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