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Structural basis for BPAG1e binding to integrin α6ß4 in hemidesmosomes

AutorManso, José A. ; Carballido Vázquez, Ana M. ; García-Rubio, Inés; Pereda, José M. de
Fecha de publicación2015
CitaciónXXXVIII SEBBM (2015)
ResumenHemidesmosomes (HDs) are junctional complexes that mediate the stable adhesion of epithelial cells to the basement membrane by linking the extracellular matrix to the intermediate filament system of the cytoskeleton. In (pseudo)stratified epithelia HDs contain integrin α6ß4, the bullous pemphigoid antigen 2 (BPAG2), the tetraspanin CD151, plectin, and BPAG1e. HDs are dynamic complexes that are disassembled during wound healing and carcinoma invasion in a process that involves phosphorylation of the ß4 subunit. BPAG1e and plectin belong to the plakin family of cytolinkers and connect the integrin α6ß4 to the cytokeratins. BPAG1e interacts with the third and fourth FnIII domains (FnIII-3,4) of the ß4 cytoplasmic moiety. We have recently elucidated the structure of the FnIII-3,4 of ß4 by combining hybrid methods, which revealed a stable arrangement of the two FnIII domains. To understand how BPAG1e interacts with the ß4 cytodomain, first we have mapped in detail the reciprocal binding sites in BPAG1e and ß4. Binding to ß4 is mediated by a segment of ~30 residues near the N-terminus of BPAG1e. Complementarily, using structure-based mutagenesis we have found that residues in ß4 that are important for BPAG1e-binding cluster on an evolutionary conserved surface of the FnIII-3,4 structure. Next, we have elucidated the crystal structure to 1.6 Å resolution of the FnIII-3,4 of ß4 bound to a fragment of BPAG1e. The structure of the complex is in agreement with the mutagenesis data and reveals residues that mediate key interactions. A phospho-mimetic mutation in BPAG1e inhibits binding to beta4 suggesting that phosphorylation of BPAG1e might contribute to the regulation of HD stability.
DescripciónResumen del póster presentado al XXXVIII Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Valencia (España) del 7 al 10 de septiembre de 2015.
URIhttp://hdl.handle.net/10261/136151
Aparece en las colecciones: (IBMCC) Comunicaciones congresos
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