Formation of Virus-like Clusters Is an Intrinsic Property of the Tumor Necrosis Factor Family Member BAFF (B Cell Activating Factor)†
Identifieur interne : 002D75 ( Main/Exploration ); précédent : 002D74; suivant : 002D76Formation of Virus-like Clusters Is an Intrinsic Property of the Tumor Necrosis Factor Family Member BAFF (B Cell Activating Factor)†
Auteurs : Teresa G. Cachero [Suisse, États-Unis] ; Ian M. Schwartz [Suisse, États-Unis] ; Fang Qian [Suisse] ; Eric S. Day [Suisse] ; Claudia Bossen [Suisse] ; Karine Ingold [Suisse] ; Aubry Tardivel [Suisse] ; Dennis Krushinskie [Suisse] ; John Eldredge [Suisse] ; Laura Silvian [Suisse] ; Alexey Lugovskoy [Suisse] ; Graham K. Farrington [Suisse] ; Kathy Strauch [Suisse] ; Pascal Schneider [Suisse] ; Adrian Whitty [Suisse]Source :
- Biochemistry [ 0006-2960 ] ; 2006.
Abstract
The oligomeric state of BAFF (B cell activing factor), a tumor necrosis factor (TNF) family cytokine that plays a critical role in B cell development and survival, has been the subject of recent debate. Myc-tagged BAFF starting at residue Gln136 was previously reported to crystallize as trimers at pH 4.5, whereas a histidine-tagged construct of BAFF, starting at residue Ala134, formed a virus-like cluster containing 60 monomers when crystallized at pH 9.0. The formation of the BAFF 60-mer was pH dependent, requiring pH ≥ 7.0. More recently, 60-mer formation was suggested to be artificially induced by the histidine tag, and it was proposed that BAFF, like all other TNF family members, is trimeric. We report here that a construct of BAFF with no amino-terminal tag (Ala134-BAFF) can form a 60-mer in solution. Using size exclusion chromatography and static light scattering to monitor trimer to 60-mer ratios in BAFF preparations, we find that 60-mer formation is pH-dependent and requires histidine 218 within the DE loop of BAFF. Biacore measurements established that the affinity of Ala134-BAFF for the BAFF receptor BAFFR/BR3 is similar to that of myc-Gln136-BAFF, which is exclusively trimeric in solution. However, Ala134-BAFF is more efficacious than myc-Gln136-BAFF in inducing B cell proliferation in vitro. We additionally show that BAFF that is processed and secreted by 293T cells transfected with full-length BAFF, or by a histiocytic lymphoma cell line (U937) that expresses BAFF endogenously, forms a pH-dependent 60-mer in solution. Our results indicate that the formation of the 60-mer in solution by the BAFF extracellular domain is an intrinsic property of the protein, and therefore that this more active form of BAFF may be physiologically relevant.
Url:
DOI: 10.1021/bi051685o
Affiliations:
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Factor Family Member BAFF (B Cell Activating Factor)<ref type="bib" target="#bi051685oAF2">†</ref></title><author><name sortKey="Cachero, Teresa G" sort="Cachero, Teresa G" uniqKey="Cachero T" first="Teresa G." last="Cachero">Teresa G. Cachero</name><affiliation wicri:level="1"><country xml:lang="fr">Suisse</country><wicri:regionArea>Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, and Department of Biochemistry, University ofLausanne, CH-1066 Epalinges</wicri:regionArea><wicri:noRegion>CH-1066 Epalinges</wicri:noRegion></affiliation><affiliation></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea> To whom correspondence should be addressed at Altus Pharmaceuticals, Inc., 625 Putnam Ave., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Schwartz, Ian M" sort="Schwartz, Ian M" uniqKey="Schwartz I" first="Ian M." last="Schwartz">Ian M. Schwartz</name><affiliation wicri:level="1"><country xml:lang="fr">Suisse</country><wicri:regionArea>Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, and Department of Biochemistry, University ofLausanne, CH-1066 Epalinges</wicri:regionArea><wicri:noRegion>CH-1066 Epalinges</wicri:noRegion></affiliation><affiliation></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea> Current address: ImmunoGen, Inc., 128 Sidney St., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Qian, Fang" sort="Qian, Fang" uniqKey="Qian F" first="Fang" last="Qian">Fang Qian</name><affiliation wicri:level="1"><country xml:lang="fr">Suisse</country><wicri:regionArea>Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, and Department of Biochemistry, University ofLausanne, CH-1066 Epalinges</wicri:regionArea><wicri:noRegion>CH-1066 Epalinges</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Day, Eric S" sort="Day, Eric S" uniqKey="Day E" first="Eric S." last="Day">Eric S. 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Farrington</name><affiliation wicri:level="1"><country xml:lang="fr">Suisse</country><wicri:regionArea>Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, and Department of Biochemistry, University ofLausanne, CH-1066 Epalinges</wicri:regionArea><wicri:noRegion>CH-1066 Epalinges</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Strauch, Kathy" sort="Strauch, Kathy" uniqKey="Strauch K" first="Kathy" last="Strauch">Kathy Strauch</name><affiliation wicri:level="1"><country xml:lang="fr">Suisse</country><wicri:regionArea>Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, and Department of Biochemistry, University ofLausanne, CH-1066 Epalinges</wicri:regionArea><wicri:noRegion>CH-1066 Epalinges</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Schneider, Pascal" sort="Schneider, Pascal" uniqKey="Schneider P" first="Pascal" last="Schneider">Pascal Schneider</name><affiliation wicri:level="1"><country xml:lang="fr">Suisse</country><wicri:regionArea>Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, and Department of Biochemistry, University ofLausanne, CH-1066 Epalinges</wicri:regionArea><wicri:noRegion>CH-1066 Epalinges</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Whitty, Adrian" sort="Whitty, Adrian" uniqKey="Whitty A" first="Adrian" last="Whitty">Adrian Whitty</name><affiliation wicri:level="1"><country xml:lang="fr">Suisse</country><wicri:regionArea>Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, and Department of Biochemistry, University ofLausanne, CH-1066 Epalinges</wicri:regionArea><wicri:noRegion>CH-1066 Epalinges</wicri:noRegion></affiliation><affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Biochemistry</title><title level="j" type="abbrev">Biochemistry</title><idno type="ISSN">0006-2960</idno><idno type="eISSN">1520-4995</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2006</date><date type="published">2006</date><biblScope unit="vol">45</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="2006">2006</biblScope><biblScope unit="page" to="2013">2013</biblScope></imprint><idno type="ISSN">0006-2960</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-2960</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">The oligomeric state of BAFF (B cell activing factor), a tumor necrosis factor (TNF) family cytokine that plays a critical role in B cell development and survival, has been the subject of recent debate. Myc-tagged BAFF starting at residue Gln136 was previously reported to crystallize as trimers at pH 4.5, whereas a histidine-tagged construct of BAFF, starting at residue Ala134, formed a virus-like cluster containing 60 monomers when crystallized at pH 9.0. The formation of the BAFF 60-mer was pH dependent, requiring pH ≥ 7.0. More recently, 60-mer formation was suggested to be artificially induced by the histidine tag, and it was proposed that BAFF, like all other TNF family members, is trimeric. We report here that a construct of BAFF with no amino-terminal tag (Ala134-BAFF) can form a 60-mer in solution. Using size exclusion chromatography and static light scattering to monitor trimer to 60-mer ratios in BAFF preparations, we find that 60-mer formation is pH-dependent and requires histidine 218 within the DE loop of BAFF. Biacore measurements established that the affinity of Ala134-BAFF for the BAFF receptor BAFFR/BR3 is similar to that of myc-Gln136-BAFF, which is exclusively trimeric in solution. However, Ala134-BAFF is more efficacious than myc-Gln136-BAFF in inducing B cell proliferation in vitro. We additionally show that BAFF that is processed and secreted by 293T cells transfected with full-length BAFF, or by a histiocytic lymphoma cell line (U937) that expresses BAFF endogenously, forms a pH-dependent 60-mer in solution. Our results indicate that the formation of the 60-mer in solution by the BAFF extracellular domain is an intrinsic property of the protein, and therefore that this more active form of BAFF may be physiologically relevant.</div></front></TEI><affiliations><list><country><li>Suisse</li><li>États-Unis</li></country><region><li>Massachusetts</li></region></list><tree><country name="Suisse"><noRegion><name sortKey="Cachero, Teresa G" sort="Cachero, Teresa G" uniqKey="Cachero T" first="Teresa G." last="Cachero">Teresa G. Cachero</name></noRegion><name sortKey="Bossen, Claudia" sort="Bossen, Claudia" uniqKey="Bossen C" first="Claudia" last="Bossen">Claudia Bossen</name><name sortKey="Day, Eric S" sort="Day, Eric S" uniqKey="Day E" first="Eric S." last="Day">Eric S. Day</name><name sortKey="Eldredge, John" sort="Eldredge, John" uniqKey="Eldredge J" first="John" last="Eldredge">John Eldredge</name><name sortKey="Farrington, Graham K" sort="Farrington, Graham K" uniqKey="Farrington G" first="Graham K." last="Farrington">Graham K. Farrington</name><name sortKey="Ingold, Karine" sort="Ingold, Karine" uniqKey="Ingold K" first="Karine" last="Ingold">Karine Ingold</name><name sortKey="Krushinskie, Dennis" sort="Krushinskie, Dennis" uniqKey="Krushinskie D" first="Dennis" last="Krushinskie">Dennis Krushinskie</name><name sortKey="Lugovskoy, Alexey" sort="Lugovskoy, Alexey" uniqKey="Lugovskoy A" first="Alexey" last="Lugovskoy">Alexey Lugovskoy</name><name sortKey="Qian, Fang" sort="Qian, Fang" uniqKey="Qian F" first="Fang" last="Qian">Fang Qian</name><name sortKey="Schneider, Pascal" sort="Schneider, Pascal" uniqKey="Schneider P" first="Pascal" last="Schneider">Pascal Schneider</name><name sortKey="Schwartz, Ian M" sort="Schwartz, Ian M" uniqKey="Schwartz I" first="Ian M." last="Schwartz">Ian M. Schwartz</name><name sortKey="Silvian, Laura" sort="Silvian, Laura" uniqKey="Silvian L" first="Laura" last="Silvian">Laura Silvian</name><name sortKey="Strauch, Kathy" sort="Strauch, Kathy" uniqKey="Strauch K" first="Kathy" last="Strauch">Kathy Strauch</name><name sortKey="Tardivel, Aubry" sort="Tardivel, Aubry" uniqKey="Tardivel A" first="Aubry" last="Tardivel">Aubry Tardivel</name><name sortKey="Whitty, Adrian" sort="Whitty, Adrian" uniqKey="Whitty A" first="Adrian" last="Whitty">Adrian Whitty</name></country><country name="États-Unis"><region name="Massachusetts"><name sortKey="Cachero, Teresa G" sort="Cachero, Teresa G" uniqKey="Cachero T" first="Teresa G." last="Cachero">Teresa G. Cachero</name></region><name sortKey="Schwartz, Ian M" sort="Schwartz, Ian M" uniqKey="Schwartz I" first="Ian M." last="Schwartz">Ian M. Schwartz</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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