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Dimer Destabilization in Superoxide Dismutase May Result in Disease-Causing Properties: Structures of Motor Neuron Disease Mutants
More than 90 point mutations in human CuZn superoxide dismutase lead to the development of familial amyotrophic lateral sclerosis, known also as motor neuron disease. A growing body of evidence suggests that a subset of mutations located close to the dimeric interface can lead to a major destabiliza...
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Published in: | Proceedings of the National Academy of Sciences - PNAS 2004-04, Vol.101 (16), p.5976-5981 |
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creator | Hough, Michael A. Grossmann, J. Günter Antonyuk, Svetlana V. Strange, Richard W. Doucette, Peter A. Rodriguez, Jorge A. Whitson, Lisa J. Hart, P. John Hayward, Lawrence J. Valentine, Joan Selverstone Hasnain, S. Samar Petsko, Gregory A. |
description | More than 90 point mutations in human CuZn superoxide dismutase lead to the development of familial amyotrophic lateral sclerosis, known also as motor neuron disease. A growing body of evidence suggests that a subset of mutations located close to the dimeric interface can lead to a major destabilization of the mutant enzymes. We have determined the crystal structures of the Ala4Val (A4V) and Ile 113Thr (I113T) mutants to 1.9 and 1.6 Å, respectively. In the A4V structure, small changes at the dimer interface result in a substantial reorientation of the two monomers. This effect is also seen in the case of the I113T crystal structure, but to a smaller extent. X-ray solution scattering data show that in the solution state, both of the mutants undergo a more pronounced conformational change compared with wild-type superoxide dismutase (SOD) than that observed in the A4V crystal structure. Shape reconstructions from the x-ray scattering data illustrate the nature of this destabilization. Comparison of these scattering data with those for bovine CuZn SOD measured at different temperatures shows that an analogous change in the scattering profile occurs for the bovine enzyme in the temperature range of 70-80°C. These results demonstrate that the A4V and I113T mutants are substantially destabilized in comparison with wild-type SOD1, and it is possible that the pathogenic properties of this subset of familial amyotrophic lateral sclerosis mutants are at least in part due to this destabilization. |
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Günter ; Antonyuk, Svetlana V. ; Strange, Richard W. ; Doucette, Peter A. ; Rodriguez, Jorge A. ; Whitson, Lisa J. ; Hart, P. John ; Hayward, Lawrence J. ; Valentine, Joan Selverstone ; Hasnain, S. Samar ; Petsko, Gregory A.</creator><creatorcontrib>Hough, Michael A. ; Grossmann, J. Günter ; Antonyuk, Svetlana V. ; Strange, Richard W. ; Doucette, Peter A. ; Rodriguez, Jorge A. ; Whitson, Lisa J. ; Hart, P. John ; Hayward, Lawrence J. ; Valentine, Joan Selverstone ; Hasnain, S. Samar ; Petsko, Gregory A.</creatorcontrib><description>More than 90 point mutations in human CuZn superoxide dismutase lead to the development of familial amyotrophic lateral sclerosis, known also as motor neuron disease. A growing body of evidence suggests that a subset of mutations located close to the dimeric interface can lead to a major destabilization of the mutant enzymes. We have determined the crystal structures of the Ala4Val (A4V) and Ile 113Thr (I113T) mutants to 1.9 and 1.6 Å, respectively. In the A4V structure, small changes at the dimer interface result in a substantial reorientation of the two monomers. This effect is also seen in the case of the I113T crystal structure, but to a smaller extent. X-ray solution scattering data show that in the solution state, both of the mutants undergo a more pronounced conformational change compared with wild-type superoxide dismutase (SOD) than that observed in the A4V crystal structure. Shape reconstructions from the x-ray scattering data illustrate the nature of this destabilization. Comparison of these scattering data with those for bovine CuZn SOD measured at different temperatures shows that an analogous change in the scattering profile occurs for the bovine enzyme in the temperature range of 70-80°C. These results demonstrate that the A4V and I113T mutants are substantially destabilized in comparison with wild-type SOD1, and it is possible that the pathogenic properties of this subset of familial amyotrophic lateral sclerosis mutants are at least in part due to this destabilization.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0305143101</identifier><identifier>PMID: 15056757</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - enzymology ; Amyotrophic Lateral Sclerosis - genetics ; Atoms ; Biological Sciences ; Crystal structure ; Crystallography, X-Ray ; Dimerization ; Dimers ; Enzymes ; Molecules ; Monomers ; Motor neuron disease ; Mutation ; Scattering, Radiation ; Superoxide Dismutase - chemistry ; Superoxide Dismutase - genetics ; Superoxide Dismutase - metabolism ; Superoxides ; Ungulates</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2004-04, Vol.101 (16), p.5976-5981</ispartof><rights>Copyright 1993/2004 The National Academy of Sciences of the United States of America</rights><rights>Copyright © 2004, The National Academy of Sciences 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c565t-c6084f40702ada928c41e81335bcd522127c22c7a9503c15417b8daf6b29f33a3</citedby><cites>FETCH-LOGICAL-c565t-c6084f40702ada928c41e81335bcd522127c22c7a9503c15417b8daf6b29f33a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/101/16.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3371949$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3371949$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829,58593,58826</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15056757$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hough, Michael A.</creatorcontrib><creatorcontrib>Grossmann, J. Günter</creatorcontrib><creatorcontrib>Antonyuk, Svetlana V.</creatorcontrib><creatorcontrib>Strange, Richard W.</creatorcontrib><creatorcontrib>Doucette, Peter A.</creatorcontrib><creatorcontrib>Rodriguez, Jorge A.</creatorcontrib><creatorcontrib>Whitson, Lisa J.</creatorcontrib><creatorcontrib>Hart, P. John</creatorcontrib><creatorcontrib>Hayward, Lawrence J.</creatorcontrib><creatorcontrib>Valentine, Joan Selverstone</creatorcontrib><creatorcontrib>Hasnain, S. Samar</creatorcontrib><creatorcontrib>Petsko, Gregory A.</creatorcontrib><title>Dimer Destabilization in Superoxide Dismutase May Result in Disease-Causing Properties: Structures of Motor Neuron Disease Mutants</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>More than 90 point mutations in human CuZn superoxide dismutase lead to the development of familial amyotrophic lateral sclerosis, known also as motor neuron disease. A growing body of evidence suggests that a subset of mutations located close to the dimeric interface can lead to a major destabilization of the mutant enzymes. We have determined the crystal structures of the Ala4Val (A4V) and Ile 113Thr (I113T) mutants to 1.9 and 1.6 Å, respectively. In the A4V structure, small changes at the dimer interface result in a substantial reorientation of the two monomers. This effect is also seen in the case of the I113T crystal structure, but to a smaller extent. X-ray solution scattering data show that in the solution state, both of the mutants undergo a more pronounced conformational change compared with wild-type superoxide dismutase (SOD) than that observed in the A4V crystal structure. Shape reconstructions from the x-ray scattering data illustrate the nature of this destabilization. Comparison of these scattering data with those for bovine CuZn SOD measured at different temperatures shows that an analogous change in the scattering profile occurs for the bovine enzyme in the temperature range of 70-80°C. These results demonstrate that the A4V and I113T mutants are substantially destabilized in comparison with wild-type SOD1, and it is possible that the pathogenic properties of this subset of familial amyotrophic lateral sclerosis mutants are at least in part due to this destabilization.</description><subject>Amyotrophic lateral sclerosis</subject><subject>Amyotrophic Lateral Sclerosis - enzymology</subject><subject>Amyotrophic Lateral Sclerosis - genetics</subject><subject>Atoms</subject><subject>Biological Sciences</subject><subject>Crystal structure</subject><subject>Crystallography, X-Ray</subject><subject>Dimerization</subject><subject>Dimers</subject><subject>Enzymes</subject><subject>Molecules</subject><subject>Monomers</subject><subject>Motor neuron disease</subject><subject>Mutation</subject><subject>Scattering, Radiation</subject><subject>Superoxide Dismutase - chemistry</subject><subject>Superoxide Dismutase - genetics</subject><subject>Superoxide Dismutase - metabolism</subject><subject>Superoxides</subject><subject>Ungulates</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNqFkUtvEzEURkcIRNPCmg0CrxCbaa9f43ElFijhJTWAKKwtj8dTXE3GwY-qZckvx1GiBDawsnR9zidff1X1BMMpBkHP1pOOp0CBY0Yx4HvVDIPEdcMk3K9mAETULSPsqDqO8RoAJG_hYXWEOfBGcDGrfi3cyga0sDHpzo3up07OT8hN6DKvbfC3rrdo4eIqJx0tWuo79MXGPKYNUua2TOu5ztFNV-hz8MVJzsZzdJlCNikHG5Ef0NInH9BHm4Pfa2hZMqcUH1UPBj1G-3h3nlTf3r75On9fX3x692H--qI2vOGpNg20bGAggOheS9Iahm2LKeWd6TkhmAhDiBFacqAGc4ZF1_Z6aDoiB0o1PalebXPXuVvZ3tgpBT2qdXArHe6U1079fTO57-rK3ygquYS2-C92fvA_cvkwtXLR2HHUk_U5KoHbBmjD_gtiIbnARBbwbAua4GMMdtg_BoPa9Ks2_apDv8V49ucOB35XaAGe74CNeYjDCjeKS9EU4uW_CTXkcUz2NhX06Ra9jqW-PUupwJJJ-hs0MsWi</recordid><startdate>20040420</startdate><enddate>20040420</enddate><creator>Hough, Michael A.</creator><creator>Grossmann, J. Günter</creator><creator>Antonyuk, Svetlana V.</creator><creator>Strange, Richard W.</creator><creator>Doucette, Peter A.</creator><creator>Rodriguez, Jorge A.</creator><creator>Whitson, Lisa J.</creator><creator>Hart, P. John</creator><creator>Hayward, Lawrence J.</creator><creator>Valentine, Joan Selverstone</creator><creator>Hasnain, S. Samar</creator><creator>Petsko, Gregory A.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20040420</creationdate><title>Dimer Destabilization in Superoxide Dismutase May Result in Disease-Causing Properties: Structures of Motor Neuron Disease Mutants</title><author>Hough, Michael A. ; Grossmann, J. Günter ; Antonyuk, Svetlana V. ; Strange, Richard W. ; Doucette, Peter A. ; Rodriguez, Jorge A. ; Whitson, Lisa J. ; Hart, P. John ; Hayward, Lawrence J. ; Valentine, Joan Selverstone ; Hasnain, S. 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Günter</creatorcontrib><creatorcontrib>Antonyuk, Svetlana V.</creatorcontrib><creatorcontrib>Strange, Richard W.</creatorcontrib><creatorcontrib>Doucette, Peter A.</creatorcontrib><creatorcontrib>Rodriguez, Jorge A.</creatorcontrib><creatorcontrib>Whitson, Lisa J.</creatorcontrib><creatorcontrib>Hart, P. John</creatorcontrib><creatorcontrib>Hayward, Lawrence J.</creatorcontrib><creatorcontrib>Valentine, Joan Selverstone</creatorcontrib><creatorcontrib>Hasnain, S. Samar</creatorcontrib><creatorcontrib>Petsko, Gregory A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hough, Michael A.</au><au>Grossmann, J. Günter</au><au>Antonyuk, Svetlana V.</au><au>Strange, Richard W.</au><au>Doucette, Peter A.</au><au>Rodriguez, Jorge A.</au><au>Whitson, Lisa J.</au><au>Hart, P. John</au><au>Hayward, Lawrence J.</au><au>Valentine, Joan Selverstone</au><au>Hasnain, S. Samar</au><au>Petsko, Gregory A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dimer Destabilization in Superoxide Dismutase May Result in Disease-Causing Properties: Structures of Motor Neuron Disease Mutants</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2004-04-20</date><risdate>2004</risdate><volume>101</volume><issue>16</issue><spage>5976</spage><epage>5981</epage><pages>5976-5981</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><notes>ObjectType-Article-1</notes><notes>ObjectType-Feature-2</notes><notes>To whom correspondence should be addressed at: CCLRC Daresbury Laboratory, Keckwick Lane, Warrington WA4 4AD, United Kingdom. E-mail: s.hasnain@dl.ac.uk.</notes><notes>Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved January 26, 2004</notes><notes>This paper was submitted directly (Track II) to the PNAS office.</notes><notes>Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org [PDB ID codes 1UXM (A4V) and 1UXL (I113T)].</notes><notes>Abbreviations: ALS, amyotrophic lateral sclerosis; FALS, familial ALS; SALS, sporadic ALS; SOD, superoxide dismutase; wtSOD, wild-type SOD; BSOD, bovine SOD; A4V, the Ala4Val mutant of SOD1; I113T, the Ile113Thr mutant of SOD1.</notes><notes>See Commentary on page 5701.</notes><abstract>More than 90 point mutations in human CuZn superoxide dismutase lead to the development of familial amyotrophic lateral sclerosis, known also as motor neuron disease. A growing body of evidence suggests that a subset of mutations located close to the dimeric interface can lead to a major destabilization of the mutant enzymes. We have determined the crystal structures of the Ala4Val (A4V) and Ile 113Thr (I113T) mutants to 1.9 and 1.6 Å, respectively. In the A4V structure, small changes at the dimer interface result in a substantial reorientation of the two monomers. This effect is also seen in the case of the I113T crystal structure, but to a smaller extent. X-ray solution scattering data show that in the solution state, both of the mutants undergo a more pronounced conformational change compared with wild-type superoxide dismutase (SOD) than that observed in the A4V crystal structure. Shape reconstructions from the x-ray scattering data illustrate the nature of this destabilization. Comparison of these scattering data with those for bovine CuZn SOD measured at different temperatures shows that an analogous change in the scattering profile occurs for the bovine enzyme in the temperature range of 70-80°C. These results demonstrate that the A4V and I113T mutants are substantially destabilized in comparison with wild-type SOD1, and it is possible that the pathogenic properties of this subset of familial amyotrophic lateral sclerosis mutants are at least in part due to this destabilization.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>15056757</pmid><doi>10.1073/pnas.0305143101</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - enzymology Amyotrophic Lateral Sclerosis - genetics Atoms Biological Sciences Crystal structure Crystallography, X-Ray Dimerization Dimers Enzymes Molecules Monomers Motor neuron disease Mutation Scattering, Radiation Superoxide Dismutase - chemistry Superoxide Dismutase - genetics Superoxide Dismutase - metabolism Superoxides Ungulates |
title | Dimer Destabilization in Superoxide Dismutase May Result in Disease-Causing Properties: Structures of Motor Neuron Disease Mutants |
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