Structure of the Tuberous Sclerosis Complex 2 (TSC2) N Terminus Provides Insight into Complex Assembly and Tuberous Sclerosis Pathogenesis
DC Element | Wert | Sprache |
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dc.contributor.author | Zech, Reinhard | |
dc.contributor.author | Kiontke, Stephan | |
dc.contributor.author | Mueller, Uwe | |
dc.contributor.author | Oeckinghaus, Andrea | |
dc.contributor.author | Kuemmel, Daniel | |
dc.date.accessioned | 2021-12-23T16:17:13Z | - |
dc.date.available | 2021-12-23T16:17:13Z | - |
dc.date.issued | 2016 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/12262 | - |
dc.description.abstract | Tuberous sclerosis complex (TSC) is caused by mutations in the TSC1 and TSC2 tumor suppressor genes. The gene products hamartin and tuberin form the TSC complex that acts as GTPase-activating protein for Rheb and negatively regulates the mammalian target of rapamycin complex 1 (mTORC1). Tuberin contains a RapGAP homology domain responsible for inactivation of Rheb, but functions of other protein domains remain elusive. Here we show that the TSC2 N terminus interacts with the TSC1 C terminus to mediate complex formation. The structure of the TSC2 N-terminal domain from Chaetomium thermophilum and a homology model of the human tuberin N terminus are presented. We characterize the molecular requirements for TSC1-TSC2 interactions and analyze pathological point mutations in tuberin. Many mutations are structural and produce improperly folded protein, explaining their effect in pathology, but we identify one point mutant that abrogates complex formation without affecting protein structure. We provide the first structural information on TSC2/tuberin with novel insight into the molecular function. | |
dc.description.sponsorship | Helmholtz-Zentrum BerlinHelmholtz Association; We are grateful to Saskia Schuback and Nadine Lottmann for excellent technical support and the Ungermann lab for help and suggestions. We thank the staff at Beamline ID23-1 at the European Synchrotron Radiation Facility and BL 14.1 at BESSY II for assistance during data collection, the Helmholtz-Zentrum Berlin for the allocation of synchrotron radiation beamtime and acknowledge the financial support by Helmholtz-Zentrum Berlin. | |
dc.language.iso | en | |
dc.publisher | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | |
dc.relation.ispartof | JOURNAL OF BIOLOGICAL CHEMISTRY | |
dc.subject | Biochemistry & Molecular Biology | |
dc.subject | DOMAIN | |
dc.subject | FUNCTIONAL ASSESSMENT | |
dc.subject | GROWTH | |
dc.subject | GTPASE | |
dc.subject | HAMARTIN | |
dc.subject | MTORC1 | |
dc.subject | PATHOLOGICAL MUTATIONS | |
dc.subject | PROTEIN | |
dc.subject | protein structure | |
dc.subject | protein-protein interaction | |
dc.subject | signaling | |
dc.subject | SWISS-MODEL | |
dc.subject | TSC1-TSC2 COMPLEX | |
dc.subject | tuberin | |
dc.subject | tuberous sclerosis complex (TSC) | |
dc.subject | x-ray crystallography | |
dc.title | Structure of the Tuberous Sclerosis Complex 2 (TSC2) N Terminus Provides Insight into Complex Assembly and Tuberous Sclerosis Pathogenesis | |
dc.type | journal article | |
dc.identifier.doi | 10.1074/jbc.M116.732446 | |
dc.identifier.isi | ISI:000383243100024 | |
dc.description.volume | 291 | |
dc.description.issue | 38 | |
dc.description.startpage | 20008 | |
dc.description.endpage | 20020 | |
dc.contributor.researcherid | AAW-9933-2020 | |
dc.identifier.eissn | 1083351X | |
dc.publisher.place | 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA | |
dcterms.isPartOf.abbreviation | J. Biol. Chem. | |
dcterms.oaStatus | Green Published, hybrid | |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.netid | KuDa343 | - |
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geprüft am 07.06.2024