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3t3l

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Revision as of 12:39, 5 August 2016

1.15 A structure of human frataxin variant Q153A

Structural highlights

3t3l is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	3t3j, 3t3k, 3t3t, 3t3x
Gene:	FXN, FRDA, X25 (HUMAN)
Activity:	Ferroxidase, with EC number 1.16.3.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[FRDA_HUMAN] Defects in FXN are the cause of Friedreich ataxia (FRDA) [MIM:229300]. FRDA is an autosomal recessive, progressive degenerative disease characterized by neurodegeneration and cardiomyopathy it is the most common inherited ataxia. The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and hammer toe. In most patients, FRDA is due to GAA triplet repeat expansions in the first intron of the frataxin gene. But in some cases the disease is due to mutations in the coding region.[:][:]^[1] ^[2] ^[3] ^[4] [:]^[5] ^[6]

Function

[FRDA_HUMAN] Promotes the biosynthesis of heme and assembly and repair of iron-sulfur clusters by delivering Fe(2+) to proteins involved in these pathways. May play a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe(2+) to Fe(3+); the oligomeric form but not the monomeric form has in vitro ferroxidase activity. May be able to store large amounts of iron in the form of a ferrihydrite mineral by oligomerization; however, the physiological relevance is unsure as reports are conflicting and the function has only been shown using heterologous overexpression systems. Modulates the RNA-binding activity of ACO1.^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14] ^[15]

Publication Abstract from PubMed

Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease associated with the loss of function of the protein frataxin (FXN) that results from low FXN levels due to a GAA triplet repeat expansion or, occasionally, from missense mutations in the FXN gene. Here biochemical and structural properties of FXN variants, including three FRDA missense mutations (N146K, Q148R, and R165C) and three related mutants (N146A, Q148G, and Q153A), were determined in an effort to understand the structural basis for the loss of function. In vitro assays revealed that although the three FRDA missense mutations exhibited similar losses of cysteine desulfurase and Fe-S cluster assembly activities, the causes for these activation defects were distinct. The R165C variant exhibited a k(cat)/K(M) higher than that of native FXN but weak binding to the NFS1, ISD11, and ISCU2 (SDU) complex, whereas the Q148R variant exhibited the lowest k(cat)/K(M) of the six tested FXN variants and only a modest binding deficiency. The order of the FXN binding affinities for the SDU Fe-S assembly complex was as follows: FXN > Q148R > N146A > Q148G > N146K > Q153A > R165C. Four different classes of FXN variants were identified on the basis of their biochemical properties. Together, these structure-function studies reveal determinants for the binding and allosteric activation of the Fe-S assembly complex and provide insight into how FRDA missense mutations are functionally compromised.

Structure-Function Analysis of Friedreich's Ataxia Mutants Reveals Determinants of Frataxin Binding and Activation of the Fe-S Assembly Complex.,Bridwell-Rabb J, Winn AM, Barondeau DP Biochemistry. 2011 Aug 2. PMID:21776984^[16]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bidichandani SI, Ashizawa T, Patel PI. Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. Am J Hum Genet. 1997 May;60(5):1251-6. PMID:9150176
↑ Bartolo C, Mendell JR, Prior TW. Identification of a missense mutation in a Friedreich's ataxia patient: implications for diagnosis and carrier studies. Am J Med Genet. 1998 Oct 12;79(5):396-9. PMID:9779809
↑ Forrest SM, Knight M, Delatycki MB, Paris D, Williamson R, King J, Yeung L, Nassif N, Nicholson GA. The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene. Neurogenetics. 1998 Aug;1(4):253-7. PMID:10732799
↑ Cossee M, Durr A, Schmitt M, Dahl N, Trouillas P, Allinson P, Kostrzewa M, Nivelon-Chevallier A, Gustavson KH, Kohlschutter A, Muller U, Mandel JL, Brice A, Koenig M, Cavalcanti F, Tammaro A, De Michele G, Filla A, Cocozza S, Labuda M, Montermini L, Poirier J, Pandolfo M. Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes. Ann Neurol. 1999 Feb;45(2):200-6. PMID:9989622
↑ Al-Mahdawi S, Pook M, Chamberlain S. A novel missense mutation (L198R) in the Friedreich's ataxia gene. Hum Mutat. 2000 Jul;16(1):95. PMID:10874325 doi:<95::AID-HUMU29>3.0.CO;2-E 10.1002/1098-1004(200007)16:1<95::AID-HUMU29>3.0.CO;2-E
↑ Calmels N, Schmucker S, Wattenhofer-Donze M, Martelli A, Vaucamps N, Reutenauer L, Messaddeq N, Bouton C, Koenig M, Puccio H. The first cellular models based on frataxin missense mutations that reproduce spontaneously the defects associated with Friedreich ataxia. PLoS One. 2009 Jul 24;4(7):e6379. PMID:19629184 doi:10.1371/journal.pone.0006379
↑ Condo I, Malisan F, Guccini I, Serio D, Rufini A, Testi R. Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin. Hum Mol Genet. 2010 Jan 20. PMID:20053667 doi:ddp592
↑ Cavadini P, O'Neill HA, Benada O, Isaya G. Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Hum Mol Genet. 2002 Feb 1;11(3):217-27. PMID:11823441
↑ Nichol H, Gakh O, O'Neill HA, Pickering IJ, Isaya G, George GN. Structure of frataxin iron cores: an X-ray absorption spectroscopic study. Biochemistry. 2003 May 27;42(20):5971-6. PMID:12755598 doi:10.1021/bi027021l
↑ Yoon T, Cowan JA. Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins. J Am Chem Soc. 2003 May 21;125(20):6078-84. PMID:12785837 doi:10.1021/ja027967i
↑ Yoon T, Cowan JA. Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. J Biol Chem. 2004 Jun 18;279(25):25943-6. Epub 2004 Apr 27. PMID:15123683 doi:10.1074/jbc.C400107200
↑ Bulteau AL, O'Neill HA, Kennedy MC, Ikeda-Saito M, Isaya G, Szweda LI. Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science. 2004 Jul 9;305(5681):242-5. PMID:15247478 doi:10.1126/science.1098991
↑ O'Neill HA, Gakh O, Park S, Cui J, Mooney SM, Sampson M, Ferreira GC, Isaya G. Assembly of human frataxin is a mechanism for detoxifying redox-active iron. Biochemistry. 2005 Jan 18;44(2):537-45. PMID:15641778 doi:10.1021/bi048459j
↑ Schoenfeld RA, Napoli E, Wong A, Zhan S, Reutenauer L, Morin D, Buckpitt AR, Taroni F, Lonnerdal B, Ristow M, Puccio H, Cortopassi GA. Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells. Hum Mol Genet. 2005 Dec 15;14(24):3787-99. Epub 2005 Oct 20. PMID:16239244 doi:10.1093/hmg/ddi393
↑ Condo I, Ventura N, Malisan F, Tomassini B, Testi R. A pool of extramitochondrial frataxin that promotes cell survival. J Biol Chem. 2006 Jun 16;281(24):16750-6. Epub 2006 Apr 11. PMID:16608849 doi:M511960200
↑ Bridwell-Rabb J, Winn AM, Barondeau DP. Structure-Function Analysis of Friedreich's Ataxia Mutants Reveals Determinants of Frataxin Binding and Activation of the Fe-S Assembly Complex. Biochemistry. 2011 Aug 2. PMID:21776984 doi:10.1021/bi200895k

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3t3l"

@@ Line 1: / Line 1: @@
 ==1.15 A structure of human frataxin variant Q153A==
 <StructureSection load='3t3l' size='340' side='right' caption='[[3t3l]], [[Resolution|resolution]] 1.15&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3t3l]] is a 1 chain structure with 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=3T3L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T3L FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3t3l]] 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=3T3L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T3L FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3t3j|3t3j]], [[3t3k|3t3k]], [[3t3t|3t3t]], [[3t3x|3t3x]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FXN, FRDA, X25 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FXN, FRDA, X25 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ferroxidase Ferroxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.16.3.1 1.16.3.1] </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=3t3l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t3l OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3t3l RCSB], [http://www.ebi.ac.uk/pdbsum/3t3l PDBsum]</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=3t3l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t3l OCA], [http://pdbe.org/3t3l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3t3l RCSB], [http://www.ebi.ac.uk/pdbsum/3t3l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3t3l ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 22: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3t3l" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
@@ Line 26: / Line 28: @@
 </StructureSection>
 [[Category: Ferroxidase]]
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Barondeau, D P]]
 [[Category: Bridwell-Rabb, J]]

3t3l

From Proteopedia

Revision as of 12:39, 5 August 2016

1.15 A structure of human frataxin variant Q153A

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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