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| - | [[Image:1aos.gif|left|200px]]<br /><applet load="1aos" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1aos, resolution 4.2Å" /> | |
| - | '''HUMAN ARGININOSUCCINATE LYASE'''<br /> | |
| | | | |
| - | ==Overview== | + | ==HUMAN ARGININOSUCCINATE LYASE== |
| - | Intragenic complementation has been observed at the argininosuccinate lyase (ASL) locus. Intragenic complementation is a phenomenon that occurs when a multimeric protein is formed from subunits produced by different mutant alleles of a gene. The resulting hybrid protein exhibits enzymatic activity that is greater than that found in the oligomeric proteins produced by each mutant allele alone. The mutations involved in the most successful complementation event observed in ASL deficiency were found to be an aspartate to glycine mutation at codon 87 of one allele (D87G) coupled with a glutamine to arginine mutation at codon 286 of the other (Q286R). To understand the structural basis of the Q286R:D87G intragenic complementation event at the ASL locus, we have determined the x-ray crystal structure of recombinant human ASL at 4. 0 A resolution. The structure has been refined to an R factor of 18. 8%. Two monomers related by a noncrystallographic 2-fold axis comprise the asymmetric unit, and a crystallographic 2-fold axis of space group P3121 completes the tetramer. Each of the four active sites is composed of residues from three monomers. Structural mapping of the Q286R and D87G mutations indicate that both are near the active site and each is contributed by a different monomer. Thus when mutant monomers combine randomly such that one active site contains both mutations, it is required by molecular symmetry that another active site exists with no mutations. These "native" active sites give rise to the observed partial recovery of enzymatic activity.
| + | <StructureSection load='1aos' size='340' side='right'caption='[[1aos]], [[Resolution|resolution]] 4.20Å' scene=''> |
| - | | + | == Structural highlights == |
| - | ==Disease== | + | <table><tr><td colspan='2'>[[1aos]] is a 2 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=1AOS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1AOS FirstGlance]. <br> |
| - | Known disease associated with this structure: Argininosuccinic aciduria OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608310 608310]]
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 4.2Å</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=1aos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1aos OCA], [https://pdbe.org/1aos PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1aos RCSB], [https://www.ebi.ac.uk/pdbsum/1aos PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1aos ProSAT]</span></td></tr> |
| - | ==About this Structure== | + | </table> |
| - | 1AOS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Argininosuccinate_lyase Argininosuccinate lyase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.3.2.1 4.3.2.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1AOS OCA].
| + | == Disease == |
| - | | + | [https://www.uniprot.org/uniprot/ARLY_HUMAN ARLY_HUMAN] Defects in ASL are the cause of arginosuccinic aciduria (ARGINSA) [MIM:[https://omim.org/entry/207900 207900]. An autosomal recessive disorder of the urea cycle. The disease is characterized by mental and physical retardation, liver enlargement, skin lesions, dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red, convulsions, and episodic unconsciousness.<ref>PMID:1705937</ref> <ref>PMID:2263616</ref> <ref>PMID:12408190</ref> <ref>PMID:17326097</ref> |
| - | ==Reference== | + | == Function == |
| - | Human argininosuccinate lyase: a structural basis for intragenic complementation., Turner MA, Simpson A, McInnes RR, Howell PL, Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9063-8. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9256435 9256435]
| + | [https://www.uniprot.org/uniprot/ARLY_HUMAN ARLY_HUMAN] |
| - | [[Category: Argininosuccinate lyase]]
| + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ao/1aos_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <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=1aos ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Howell, P L.]] | + | [[Category: Howell PL]] |
| - | [[Category: Mcinnes, R R.]] | + | [[Category: Mcinnes RR]] |
| - | [[Category: Simpson, A.]] | + | [[Category: Simpson A]] |
| - | [[Category: Turner, M A.]] | + | [[Category: Turner MA]] |
| - | [[Category: arginine biosynthesis]]
| + | |
| - | [[Category: lyase]]
| + | |
| - | [[Category: urea cycle]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:46:46 2008''
| + | |
| Structural highlights
Disease
ARLY_HUMAN Defects in ASL are the cause of arginosuccinic aciduria (ARGINSA) [MIM:207900. An autosomal recessive disorder of the urea cycle. The disease is characterized by mental and physical retardation, liver enlargement, skin lesions, dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red, convulsions, and episodic unconsciousness.[1] [2] [3] [4]
Function
ARLY_HUMAN
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
References
- ↑ Barbosa P, Cialkowski M, O'Brien WE. Analysis of naturally occurring and site-directed mutations in the argininosuccinate lyase gene. J Biol Chem. 1991 Mar 15;266(8):5286-90. PMID:1705937
- ↑ Walker DC, McCloskey DA, Simard LR, McInnes RR. Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9625-9. PMID:2263616
- ↑ Kleijer WJ, Garritsen VH, Linnebank M, Mooyer P, Huijmans JG, Mustonen A, Simola KO, Arslan-Kirchner M, Battini R, Briones P, Cardo E, Mandel H, Tschiedel E, Wanders RJ, Koch HG. Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in five unrelated families. J Inherit Metab Dis. 2002 Sep;25(5):399-410. PMID:12408190
- ↑ Trevisson E, Salviati L, Baldoin MC, Toldo I, Casarin A, Sacconi S, Cesaro L, Basso G, Burlina AB. Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene. Hum Mutat. 2007 Jul;28(7):694-702. PMID:17326097 doi:10.1002/humu.20498
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