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1.
Nature ; 457(7232): 1019-22, 2009 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-19118384

RESUMEN

The death inducing signalling complex (DISC) formed by Fas receptor, FADD (Fas-associated death domain protein) and caspase 8 is a pivotal trigger of apoptosis. The Fas-FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains of Fas and FADD is at the centre of DISC formation. Thus, characterizing the mechanistic basis for the Fas-FADD interaction is crucial for understanding DISC signalling but has remained unclear largely because of a lack of structural data. We have successfully formed and isolated the human Fas-FADD death domain complex and report the 2.7 A crystal structure. The complex shows a tetrameric arrangement of four FADD death domains bound to four Fas death domains. We show that an opening of the Fas death domain exposes the FADD binding site and simultaneously generates a Fas-Fas bridge. The result is a regulatory Fas-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. In addition to depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signalling solely by oligomerization and clustering events.


Asunto(s)
Proteína de Dominio de Muerte Asociada a Fas/química , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Agregación de Receptores , Transducción de Señal , Receptor fas/química , Receptor fas/metabolismo , Cristalografía por Rayos X , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/química , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/metabolismo , Humanos , Modelos Moleculares , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismo
2.
Nat Struct Mol Biol ; 18(12): 1381-7, 2011 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-22081014

RESUMEN

Members of the novel SH2-containing protein (NSP) and Crk-associated substrate (Cas) protein families form multidomain signaling platforms that mediate cell migration and invasion through a collection of distinct signaling motifs. Members of each family interact via their respective C-terminal domains, but the mechanism of this association has remained enigmatic. Here we present the crystal structures of the C-terminal domain from the NSP protein BCAR3 and the complex of NSP3 with p130Cas. BCAR3 adopts the Cdc25-homology fold of Ras GTPase exchange factors, but it has a 'closed' conformation incapable of enzymatic activity. The structure of the NSP3-p130Cas complex reveals that this closed conformation is instrumental for interaction of NSP proteins with a focal adhesion-targeting domain present in Cas proteins. This enzyme-to-adaptor conversion enables high-affinity, yet promiscuous, interactions between NSP and Cas proteins and represents an unprecedented mechanistic paradigm linking cellular signaling networks.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/química , Proteína Sustrato Asociada a CrK/química , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Sitios de Unión , Secuencia Conservada , Proteína Sustrato Asociada a CrK/metabolismo , Factores de Intercambio de Guanina Nucleótido , Humanos , Modelos Moleculares , Estructura Terciaria de Proteína
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