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Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 binding site.
Lipper, Colin H; Gabriel, Khal-Hentz; Seegar, Tom C M; Dürr, Katharina L; Tomlinson, Michael G; Blacklow, Stephen C.
Afiliação
  • Lipper CH; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Gabriel KH; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
  • Seegar TCM; University of Cincinnati School of Medicine, Department of Molecular Genetics, Biochemistry, and Microbiology, Cincinnati, OH 45267, USA.
  • Dürr KL; OMass Therapeutics, Oxford OX4 4GE, UK.
  • Tomlinson MG; School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.
  • Blacklow SC; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: stephen_blacklow@hms.harvard.edu.
Structure ; 30(2): 206-214.e4, 2022 02 03.
Article em En | MEDLINE | ID: mdl-34739841
Tetraspanins are four-pass transmembrane proteins that function by regulating trafficking of partner proteins and organizing signaling complexes in the membrane. Tspan15, one of a six-member TspanC8 subfamily, forms a complex that regulates the trafficking, maturation, and substrate selectivity of the transmembrane protease ADAM10, an essential enzyme in mammalian physiology that cleaves a wide variety of membrane-anchored substrates, including Notch receptors, amyloid precursor protein, cadherins, and growth factors. We present here crystal structures of the Tspan15 large extracellular loop (LEL) required for functional association with ADAM10 both in isolation and in complex with the Fab fragment of an anti-Tspan15 antibody. Comparison of the Tspan15 LEL with other tetraspanin LEL structures shows that a core helical framework buttresses a variable region that structurally diverges among LELs. Using co-immunoprecipitation and a cellular N-cadherin cleavage assay, we identify a site on Tspan15 required for both ADAM10 binding and promoting substrate cleavage.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Antígenos CD / Caderinas / Secretases da Proteína Precursora do Amiloide / Tetraspaninas / Proteína ADAM10 / Proteínas de Membrana / Mutação Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Structure Assunto da revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Antígenos CD / Caderinas / Secretases da Proteína Precursora do Amiloide / Tetraspaninas / Proteína ADAM10 / Proteínas de Membrana / Mutação Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Structure Assunto da revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos