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Diverse Functional Consequences of Mutations in the Na+/K+-ATPase α2-Subunit Causing Familial Hemiplegic Migraine Type 2
Mutations in ATP1A2, the gene coding for the Na+/K+-ATPase α2-subunit, are associated with both familial hemiplegic migraine and sporadic cases of hemiplegic migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic hemiplegic migraine...
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Published in: | The Journal of biological chemistry 2008-11, Vol.283 (45), p.31097-31106 |
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description | Mutations in ATP1A2, the gene coding for the Na+/K+-ATPase α2-subunit, are associated with both familial hemiplegic migraine and sporadic cases of hemiplegic migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic hemiplegic migraine, including missense mutations (T263M, T376M, R383H, A606T, R763H, M829R, R834Q, R937P, and X1021R), a deletion mutant (del(K935-S940)ins(I)), and a frameshift mutation (S966fs). According to the Na+/K+-ATPase crystal structure, a subset of the mutated residues (Ala606, Arg763, Met829, and Arg834) is involved in important interdomain H-bond networks, and the C terminus of the enzyme, which is elongated by the X1021R mutation, has been implicated in voltage dependence and formation of a third Na+-binding site. Upon heterologous expression in Xenopus oocytes, the analysis of electrogenic transport properties, Rb+ uptake, and protein expression revealed pronounced and markedly diverse functional alterations in all ATP1A2 mutants. Abnormalities included a complete loss of function (T376M), impaired plasma membrane expression (del(K935-S940)ins(I) and S966fs), and altered apparent affinities for extracellular cations or reduced enzyme turnover (R383H, A606T, R763H, R834Q, and X1021R). In addition, changes in the voltage dependence of pump currents and the increased rate constants of the voltage jump-induced redistribution between E1P and E2P states were observed. Thus, mutations that disrupt distinct interdomain H-bond patterns can cause abnormal conformational flexibility and exert long range consequences on apparent cation affinities or voltage dependence. Of interest, the X1021R mutation severely impaired voltage dependence and kinetics of Na+-translocating partial reactions, corroborating the critical role of the C terminus of Na+/K+-ATPase in these processes. |
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In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic hemiplegic migraine, including missense mutations (T263M, T376M, R383H, A606T, R763H, M829R, R834Q, R937P, and X1021R), a deletion mutant (del(K935-S940)ins(I)), and a frameshift mutation (S966fs). According to the Na+/K+-ATPase crystal structure, a subset of the mutated residues (Ala606, Arg763, Met829, and Arg834) is involved in important interdomain H-bond networks, and the C terminus of the enzyme, which is elongated by the X1021R mutation, has been implicated in voltage dependence and formation of a third Na+-binding site. Upon heterologous expression in Xenopus oocytes, the analysis of electrogenic transport properties, Rb+ uptake, and protein expression revealed pronounced and markedly diverse functional alterations in all ATP1A2 mutants. Abnormalities included a complete loss of function (T376M), impaired plasma membrane expression (del(K935-S940)ins(I) and S966fs), and altered apparent affinities for extracellular cations or reduced enzyme turnover (R383H, A606T, R763H, R834Q, and X1021R). In addition, changes in the voltage dependence of pump currents and the increased rate constants of the voltage jump-induced redistribution between E1P and E2P states were observed. Thus, mutations that disrupt distinct interdomain H-bond patterns can cause abnormal conformational flexibility and exert long range consequences on apparent cation affinities or voltage dependence. Of interest, the X1021R mutation severely impaired voltage dependence and kinetics of Na+-translocating partial reactions, corroborating the critical role of the C terminus of Na+/K+-ATPase in these processes.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M802771200</identifier><identifier>PMID: 18728015</identifier><language>eng</language><publisher>Elsevier Inc</publisher><subject>Membrane Transport, Structure, Function, and Biogenesis</subject><ispartof>The Journal of biological chemistry, 2008-11, Vol.283 (45), p.31097-31106</ispartof><rights>2008 © 2008 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>Copyright © 2008, The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3880-ca13e5afe16140e71ea2850f05b29ad2fb4cb237b749d28d82fe2c452f8887843</citedby><cites>FETCH-LOGICAL-c3880-ca13e5afe16140e71ea2850f05b29ad2fb4cb237b749d28d82fe2c452f8887843</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662176/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662176/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids></links><search><creatorcontrib>Tavraz, Neslihan N.</creatorcontrib><creatorcontrib>Friedrich, Thomas</creatorcontrib><creatorcontrib>Dürr, Katharina L.</creatorcontrib><creatorcontrib>Koenderink, Jan B.</creatorcontrib><creatorcontrib>Bamberg, Ernst</creatorcontrib><creatorcontrib>Freilinger, Tobias</creatorcontrib><creatorcontrib>Dichgans, Martin</creatorcontrib><title>Diverse Functional Consequences of Mutations in the Na+/K+-ATPase α2-Subunit Causing Familial Hemiplegic Migraine Type 2</title><title>The Journal of biological chemistry</title><description>Mutations in ATP1A2, the gene coding for the Na+/K+-ATPase α2-subunit, are associated with both familial hemiplegic migraine and sporadic cases of hemiplegic migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic hemiplegic migraine, including missense mutations (T263M, T376M, R383H, A606T, R763H, M829R, R834Q, R937P, and X1021R), a deletion mutant (del(K935-S940)ins(I)), and a frameshift mutation (S966fs). According to the Na+/K+-ATPase crystal structure, a subset of the mutated residues (Ala606, Arg763, Met829, and Arg834) is involved in important interdomain H-bond networks, and the C terminus of the enzyme, which is elongated by the X1021R mutation, has been implicated in voltage dependence and formation of a third Na+-binding site. Upon heterologous expression in Xenopus oocytes, the analysis of electrogenic transport properties, Rb+ uptake, and protein expression revealed pronounced and markedly diverse functional alterations in all ATP1A2 mutants. Abnormalities included a complete loss of function (T376M), impaired plasma membrane expression (del(K935-S940)ins(I) and S966fs), and altered apparent affinities for extracellular cations or reduced enzyme turnover (R383H, A606T, R763H, R834Q, and X1021R). In addition, changes in the voltage dependence of pump currents and the increased rate constants of the voltage jump-induced redistribution between E1P and E2P states were observed. Thus, mutations that disrupt distinct interdomain H-bond patterns can cause abnormal conformational flexibility and exert long range consequences on apparent cation affinities or voltage dependence. Of interest, the X1021R mutation severely impaired voltage dependence and kinetics of Na+-translocating partial reactions, corroborating the critical role of the C terminus of Na+/K+-ATPase in these processes.</description><subject>Membrane Transport, Structure, Function, and Biogenesis</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNp1kU9vEzEQxS0EoqFw5Yrv1ab-s856L0hVIBTRAFJTiZvl9Y63U228wd6NlI_FF-lnqqMgEAfmMod57yfNe4S85WzOWVVePjRuvtZMVBUXjD0jM860LKTiP56TGWOCF7VQ-oy8SumB5Slr_pKccV0JzbiakcMH3ENMQFdTcCMOwfZ0OYQEPycIDhIdPF1Poz2eEsVAx3ugX-3F5ZeL4mrz3Wbn4y9R3E7NFHCkSzslDB1d2S32mFnXsMVdDx06usYuWgxAN4cdUPGavPC2T_Dm9z4nd6uPm-V1cfPt0-fl1U3hpNascJZLUNYDX_CSQcXBCq2YZ6oRtW2Fb0rXCFk1VVm3QrdaeBCuVMJrrStdynPy_sTdTc0WWgdhjLY3u4hbGw9msGj-vQS8N92wN2KxELxaZMD8BHBxSCmC_-PlzBxLMLkE87eEbHh3Mng7GNtFTObuVjAuc-JKSVlnhT4pID--R4gmOTzm3WIEN5p2wP_BnwCWipa7</recordid><startdate>20081107</startdate><enddate>20081107</enddate><creator>Tavraz, Neslihan N.</creator><creator>Friedrich, Thomas</creator><creator>Dürr, Katharina L.</creator><creator>Koenderink, Jan B.</creator><creator>Bamberg, Ernst</creator><creator>Freilinger, Tobias</creator><creator>Dichgans, Martin</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20081107</creationdate><title>Diverse Functional Consequences of Mutations in the Na+/K+-ATPase α2-Subunit Causing Familial Hemiplegic Migraine Type 2</title><author>Tavraz, Neslihan N. ; Friedrich, Thomas ; Dürr, Katharina L. ; Koenderink, Jan B. ; Bamberg, Ernst ; Freilinger, Tobias ; Dichgans, Martin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3880-ca13e5afe16140e71ea2850f05b29ad2fb4cb237b749d28d82fe2c452f8887843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Membrane Transport, Structure, Function, and Biogenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tavraz, Neslihan N.</creatorcontrib><creatorcontrib>Friedrich, Thomas</creatorcontrib><creatorcontrib>Dürr, Katharina L.</creatorcontrib><creatorcontrib>Koenderink, Jan B.</creatorcontrib><creatorcontrib>Bamberg, Ernst</creatorcontrib><creatorcontrib>Freilinger, Tobias</creatorcontrib><creatorcontrib>Dichgans, Martin</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tavraz, Neslihan N.</au><au>Friedrich, Thomas</au><au>Dürr, Katharina L.</au><au>Koenderink, Jan B.</au><au>Bamberg, Ernst</au><au>Freilinger, Tobias</au><au>Dichgans, Martin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Diverse Functional Consequences of Mutations in the Na+/K+-ATPase α2-Subunit Causing Familial Hemiplegic Migraine Type 2</atitle><jtitle>The Journal of biological chemistry</jtitle><date>2008-11-07</date><risdate>2008</risdate><volume>283</volume><issue>45</issue><spage>31097</spage><epage>31106</epage><pages>31097-31106</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><notes>These authors contributed equally to this work.</notes><notes>This work was supported by the Max-Planck-Gesellschaft and Deutsche Forschungsgemeinschaft Grants (DI 722/8-2, KFG K1 027, KFG K1 028, and SFB 740 TPC4, Cluster of Excellence “Unifying Concepts in Catalysis”;). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.</notes><notes>To whom correspondence should be addressed: Technical University of Berlin, Institute of Chemistry Sekr. PC-14, Strasse des 17 Juni 135, D-10623 Berlin, Germany. Tel.: 49-30-31424128; Fax: 49-30-31478600; E-mail: friedrich@chem.tu-berlin.de.</notes><abstract>Mutations in ATP1A2, the gene coding for the Na+/K+-ATPase α2-subunit, are associated with both familial hemiplegic migraine and sporadic cases of hemiplegic migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic hemiplegic migraine, including missense mutations (T263M, T376M, R383H, A606T, R763H, M829R, R834Q, R937P, and X1021R), a deletion mutant (del(K935-S940)ins(I)), and a frameshift mutation (S966fs). According to the Na+/K+-ATPase crystal structure, a subset of the mutated residues (Ala606, Arg763, Met829, and Arg834) is involved in important interdomain H-bond networks, and the C terminus of the enzyme, which is elongated by the X1021R mutation, has been implicated in voltage dependence and formation of a third Na+-binding site. Upon heterologous expression in Xenopus oocytes, the analysis of electrogenic transport properties, Rb+ uptake, and protein expression revealed pronounced and markedly diverse functional alterations in all ATP1A2 mutants. Abnormalities included a complete loss of function (T376M), impaired plasma membrane expression (del(K935-S940)ins(I) and S966fs), and altered apparent affinities for extracellular cations or reduced enzyme turnover (R383H, A606T, R763H, R834Q, and X1021R). In addition, changes in the voltage dependence of pump currents and the increased rate constants of the voltage jump-induced redistribution between E1P and E2P states were observed. Thus, mutations that disrupt distinct interdomain H-bond patterns can cause abnormal conformational flexibility and exert long range consequences on apparent cation affinities or voltage dependence. Of interest, the X1021R mutation severely impaired voltage dependence and kinetics of Na+-translocating partial reactions, corroborating the critical role of the C terminus of Na+/K+-ATPase in these processes.</abstract><pub>Elsevier Inc</pub><pmid>18728015</pmid><doi>10.1074/jbc.M802771200</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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title | Diverse Functional Consequences of Mutations in the Na+/K+-ATPase α2-Subunit Causing Familial Hemiplegic Migraine Type 2 |
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