Structural basis of the GM2 gangliosidosis B variant
To study the structural basis of the GM2 gangliosidosis B variant, we constructed the three-dimensional structures of the human β-hexosaminidase α-subunit and the heterodimer of the α- and β-subunits, Hex A, by homology modeling. The α-subunit is composed of two domains, domains I and II. Nine mutan...
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| Veröffentlicht in: | Journal of human genetics 2003-11, Vol.48 (11), p.582-589 |
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| container_title | Journal of human genetics |
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| creator | Matsuzawa, Fumiko Aikawa, Sei-ichi Sakuraba, Hitoshi Lan, Hoang Thi Ngoc Tanaka, Akemi Ohno, Kousaku Sugimoto, Yuko Ninomiya, Haruaki Doi, Hirofumi |
| description | To study the structural basis of the GM2 gangliosidosis B variant, we constructed the three-dimensional structures of the human β-hexosaminidase α-subunit and the heterodimer of the α- and β-subunits, Hex A, by homology modeling. The α-subunit is composed of two domains, domains I and II. Nine mutant models due to specific missense mutations were constructed as well and compared with the wild type to determine structural defects. These nine mutations were divided into five groups according to structural defects. R178H is deduced to affect the active site directly, because R178 is important for binding to the substrate. C458Y and W420C are predicted to cause drastic structural changes in the barrel structure carrying the active site pocket. R504C/H is deduced to introduce a disruption of an essential binding with D494 in the β-subunit for dimerization. R499C/H, located in an extra-helix, is deduced to disrupt hydrogen bonds with domain I and the barrel. R170W and L484P are deduced to affect the interface between domains I and II, causing destabilization. The structural defects reflect the biochemical abnormalities of the disease. |
| doi_str_mv | 10.1007/s10038-003-0082-7 |
| format | Article |
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The α-subunit is composed of two domains, domains I and II. Nine mutant models due to specific missense mutations were constructed as well and compared with the wild type to determine structural defects. These nine mutations were divided into five groups according to structural defects. R178H is deduced to affect the active site directly, because R178 is important for binding to the substrate. C458Y and W420C are predicted to cause drastic structural changes in the barrel structure carrying the active site pocket. R504C/H is deduced to introduce a disruption of an essential binding with D494 in the β-subunit for dimerization. R499C/H, located in an extra-helix, is deduced to disrupt hydrogen bonds with domain I and the barrel. R170W and L484P are deduced to affect the interface between domains I and II, causing destabilization. The structural defects reflect the biochemical abnormalities of the disease.</description><identifier>ISSN: 1434-5161</identifier><identifier>EISSN: 1435-232X</identifier><identifier>DOI: 10.1007/s10038-003-0082-7</identifier><identifier>PMID: 14577003</identifier><language>eng</language><publisher>Tokyo: Springer Japan</publisher><subject>Amino Acid Substitution ; beta-N-Acetylhexosaminidases - chemistry ; beta-N-Acetylhexosaminidases - genetics ; Biomedicine ; Cells, Cultured ; Defects ; Dimerization ; Gangliosidoses, GM2 - enzymology ; Gangliosidoses, GM2 - genetics ; Gangliosidosis ; Gene Expression ; Gene Function ; Gene Therapy ; Genetic Variation ; Hexosaminidase A ; Homology ; Human Genetics ; Humans ; Hydrogen bonding ; Isoenzymes - chemistry ; Isoenzymes - genetics ; Missense mutation ; Models, Molecular ; Molecular Medicine ; Mutation ; Original Article ; Protein Conformation</subject><ispartof>Journal of human genetics, 2003-11, Vol.48 (11), p.582-589</ispartof><rights>The Japan Society of Human Genetics and Springer-Verlag 2003</rights><rights>The Japan Society of Human Genetics and Springer-Verlag 2003.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c551t-4294c7881d84813b5bfe8e1ee6edd20e40145593a11b0367bdf08d5e6bb653b3</citedby><cites>FETCH-LOGICAL-c551t-4294c7881d84813b5bfe8e1ee6edd20e40145593a11b0367bdf08d5e6bb653b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10038-003-0082-7$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10038-003-0082-7$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14577003$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matsuzawa, Fumiko</creatorcontrib><creatorcontrib>Aikawa, Sei-ichi</creatorcontrib><creatorcontrib>Sakuraba, Hitoshi</creatorcontrib><creatorcontrib>Lan, Hoang Thi Ngoc</creatorcontrib><creatorcontrib>Tanaka, Akemi</creatorcontrib><creatorcontrib>Ohno, Kousaku</creatorcontrib><creatorcontrib>Sugimoto, Yuko</creatorcontrib><creatorcontrib>Ninomiya, Haruaki</creatorcontrib><creatorcontrib>Doi, Hirofumi</creatorcontrib><title>Structural basis of the GM2 gangliosidosis B variant</title><title>Journal of human genetics</title><addtitle>J Hum Genet</addtitle><addtitle>J Hum Genet</addtitle><description>To study the structural basis of the GM2 gangliosidosis B variant, we constructed the three-dimensional structures of the human β-hexosaminidase α-subunit and the heterodimer of the α- and β-subunits, Hex A, by homology modeling. The α-subunit is composed of two domains, domains I and II. Nine mutant models due to specific missense mutations were constructed as well and compared with the wild type to determine structural defects. These nine mutations were divided into five groups according to structural defects. R178H is deduced to affect the active site directly, because R178 is important for binding to the substrate. C458Y and W420C are predicted to cause drastic structural changes in the barrel structure carrying the active site pocket. R504C/H is deduced to introduce a disruption of an essential binding with D494 in the β-subunit for dimerization. R499C/H, located in an extra-helix, is deduced to disrupt hydrogen bonds with domain I and the barrel. R170W and L484P are deduced to affect the interface between domains I and II, causing destabilization. The structural defects reflect the biochemical abnormalities of the disease.</description><subject>Amino Acid Substitution</subject><subject>beta-N-Acetylhexosaminidases - chemistry</subject><subject>beta-N-Acetylhexosaminidases - genetics</subject><subject>Biomedicine</subject><subject>Cells, Cultured</subject><subject>Defects</subject><subject>Dimerization</subject><subject>Gangliosidoses, GM2 - enzymology</subject><subject>Gangliosidoses, GM2 - genetics</subject><subject>Gangliosidosis</subject><subject>Gene Expression</subject><subject>Gene Function</subject><subject>Gene Therapy</subject><subject>Genetic Variation</subject><subject>Hexosaminidase A</subject><subject>Homology</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Hydrogen bonding</subject><subject>Isoenzymes - chemistry</subject><subject>Isoenzymes - genetics</subject><subject>Missense mutation</subject><subject>Models, Molecular</subject><subject>Molecular Medicine</subject><subject>Mutation</subject><subject>Original Article</subject><subject>Protein Conformation</subject><issn>1434-5161</issn><issn>1435-232X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kM9LwzAUx4MoTqd_gBcpCN6qefm9ow6dwsSDO3gLSZt2HV07k1bwvzezw4EHD3l54X2-3zy-CF0AvgGM5W2Ilao0lngUSeUBOgFGeUooeT_86VnKQcAInYawwhEkkhyjETAuZXydIPbW-T7rem_qxJpQhaQtkm7pktkLSUrTlHXVhipvt5P75NP4yjTdGToqTB3c-e4eo8Xjw2L6lM5fZ8_Tu3macQ5dysiEZVIpyBVTQC23hVMOnBMuzwl2DMc9-IQaAIupkDYvsMq5E9YKTi0do-vBduPbj96FTq-rkLm6No1r-6Al0MmECBLBqz_gqu19E1fThBEuQBDOIgUDlfk2BO8KvfHV2vgvDVhv89RDnjoWvc1Ty6i53Dn3du3yvWIXYATIAIQ4akrn91__55oMosbE5N2v62pZkogBFvQb3e-Igw</recordid><startdate>20031101</startdate><enddate>20031101</enddate><creator>Matsuzawa, Fumiko</creator><creator>Aikawa, Sei-ichi</creator><creator>Sakuraba, Hitoshi</creator><creator>Lan, Hoang Thi Ngoc</creator><creator>Tanaka, Akemi</creator><creator>Ohno, Kousaku</creator><creator>Sugimoto, Yuko</creator><creator>Ninomiya, Haruaki</creator><creator>Doi, Hirofumi</creator><general>Springer Japan</general><general>Nature Publishing Group</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20031101</creationdate><title>Structural basis of the GM2 gangliosidosis B variant</title><author>Matsuzawa, Fumiko ; Aikawa, Sei-ichi ; Sakuraba, Hitoshi ; Lan, Hoang Thi Ngoc ; Tanaka, Akemi ; Ohno, Kousaku ; Sugimoto, Yuko ; Ninomiya, Haruaki ; Doi, Hirofumi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c551t-4294c7881d84813b5bfe8e1ee6edd20e40145593a11b0367bdf08d5e6bb653b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Amino Acid Substitution</topic><topic>beta-N-Acetylhexosaminidases - chemistry</topic><topic>beta-N-Acetylhexosaminidases - genetics</topic><topic>Biomedicine</topic><topic>Cells, Cultured</topic><topic>Defects</topic><topic>Dimerization</topic><topic>Gangliosidoses, GM2 - enzymology</topic><topic>Gangliosidoses, GM2 - genetics</topic><topic>Gangliosidosis</topic><topic>Gene Expression</topic><topic>Gene Function</topic><topic>Gene Therapy</topic><topic>Genetic Variation</topic><topic>Hexosaminidase A</topic><topic>Homology</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Hydrogen bonding</topic><topic>Isoenzymes - chemistry</topic><topic>Isoenzymes - genetics</topic><topic>Missense mutation</topic><topic>Models, Molecular</topic><topic>Molecular Medicine</topic><topic>Mutation</topic><topic>Original Article</topic><topic>Protein Conformation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Matsuzawa, Fumiko</creatorcontrib><creatorcontrib>Aikawa, Sei-ichi</creatorcontrib><creatorcontrib>Sakuraba, Hitoshi</creatorcontrib><creatorcontrib>Lan, Hoang Thi Ngoc</creatorcontrib><creatorcontrib>Tanaka, Akemi</creatorcontrib><creatorcontrib>Ohno, Kousaku</creatorcontrib><creatorcontrib>Sugimoto, Yuko</creatorcontrib><creatorcontrib>Ninomiya, Haruaki</creatorcontrib><creatorcontrib>Doi, Hirofumi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Matsuzawa, Fumiko</au><au>Aikawa, Sei-ichi</au><au>Sakuraba, Hitoshi</au><au>Lan, Hoang Thi Ngoc</au><au>Tanaka, Akemi</au><au>Ohno, Kousaku</au><au>Sugimoto, Yuko</au><au>Ninomiya, Haruaki</au><au>Doi, Hirofumi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural basis of the GM2 gangliosidosis B variant</atitle><jtitle>Journal of human genetics</jtitle><stitle>J Hum Genet</stitle><addtitle>J Hum Genet</addtitle><date>2003-11-01</date><risdate>2003</risdate><volume>48</volume><issue>11</issue><spage>582</spage><epage>589</epage><pages>582-589</pages><issn>1434-5161</issn><eissn>1435-232X</eissn><abstract>To study the structural basis of the GM2 gangliosidosis B variant, we constructed the three-dimensional structures of the human β-hexosaminidase α-subunit and the heterodimer of the α- and β-subunits, Hex A, by homology modeling. The α-subunit is composed of two domains, domains I and II. Nine mutant models due to specific missense mutations were constructed as well and compared with the wild type to determine structural defects. These nine mutations were divided into five groups according to structural defects. R178H is deduced to affect the active site directly, because R178 is important for binding to the substrate. C458Y and W420C are predicted to cause drastic structural changes in the barrel structure carrying the active site pocket. R504C/H is deduced to introduce a disruption of an essential binding with D494 in the β-subunit for dimerization. R499C/H, located in an extra-helix, is deduced to disrupt hydrogen bonds with domain I and the barrel. R170W and L484P are deduced to affect the interface between domains I and II, causing destabilization. The structural defects reflect the biochemical abnormalities of the disease.</abstract><cop>Tokyo</cop><pub>Springer Japan</pub><pmid>14577003</pmid><doi>10.1007/s10038-003-0082-7</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Substitution beta-N-Acetylhexosaminidases - chemistry beta-N-Acetylhexosaminidases - genetics Biomedicine Cells, Cultured Defects Dimerization Gangliosidoses, GM2 - enzymology Gangliosidoses, GM2 - genetics Gangliosidosis Gene Expression Gene Function Gene Therapy Genetic Variation Hexosaminidase A Homology Human Genetics Humans Hydrogen bonding Isoenzymes - chemistry Isoenzymes - genetics Missense mutation Models, Molecular Molecular Medicine Mutation Original Article Protein Conformation |
| title | Structural basis of the GM2 gangliosidosis B variant |
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