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Título:	Molecular architecture of the Bardet¿Biedl syndrome protein 2-7-9 subcomplex
Autor:	Ludlam, W. Grant; Aoba, Takuma; Cuéllar, Jorge; Bueno-Carrasco, M. Teresa; Makaju, Aman; Moody, James D.; Franklin, Sarah; Valpuesta, José M. CSIC ORCID ; Willardson, Barry M.
Palabras clave:	Protein assembly Protein complex Protein cross-linking Mass spectrometry (MS) Electron microscopy (EM) Homology modeling Bardet-Biedl syndrome Cilia transport Ciliopathy Integrated modeling
Fecha de publicación:	2019
Editor:	American Society for Biochemistry and Molecular Biology
Citación:	Journal of Biological Chemistry 294(44): 16385-16399 (2019)
Resumen:	Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by malfunctions in primary cilia resulting from mutations that disrupt the function of the BBSome, an 8-subunit complex that plays an important role in protein transport in primary cilia. To better understand the molecular basis of BBS, here we used an integrative structural modeling approach consisting of EM and chemical cross-linking coupled with MS analyses, to analyze the structure of a BBSome 2-7-9 subcomplex consisting of three homologous BBS proteins, BBS2, BBS7, and BBS9. The resulting molecular model revealed an overall structure that resembles a flattened triangle. We found that within this structure, BBS2 and BBS7 form a tight dimer through a coiled-coil interaction and that BBS9 associates with the dimer via an interaction with the α-helical domain of BBS2. Interestingly, a BBS-associated mutation of BBS2 (R632P) is located in its α-helical domain at the interface between BBS2 and BBS9, and binding experiments indicated that this mutation disrupts the BBS2-BBS9 interaction. This finding suggests that BBSome assembly is disrupted by the R632P substitution, providing molecular insights that may explain the etiology of BBS in individuals harboring this mutation.
Descripción:	© 2019 Ludlam et al.
Versión del editor:	http://dx.doi.org/10.1074/jbc.RA119.010150
URI:	http://hdl.handle.net/10261/240872
DOI:	10.1074/jbc.RA119.010150
Identificadores:	doi: 10.1074/jbc.RA119.010150 issn: 0021-9258 e-issn: 1083-351X
Aparece en las colecciones:	(CNB) Artículos