Abstract
SummaryMultidomain proteins incorporating interaction domains are central to regulation of cellular processes. The elucidation of structural organization and mechanistic insights into many of these proteins, however, remain challenging due to their inherent flexibility. Here, we describe the organization and function of four interaction domains in PLCγ1 using a combination of structural biology and biochemical approaches. Intramolecular interactions within the regulatory region center on the cSH2 domain, the only domain that also interacts with the PLC-core. In the context of fibroblast growth-factor receptor signaling, the coordinated involvement of nSH2 and cSH2 domains mediates efficient phosphorylation of PLCγ1 resulting in the interruption of an autoinhibitory interface by direct competition and, independently, dissociation of PLCγ1 from the receptor. Further structural insights into the autoinhibitory surfaces provide a framework to interpret gain-of-function mutations in PLCγ isoforms linked to immune disorders and illustrate a distinct mechanism for regulation of PLC activity by common interaction domains.
Highlights
Selective intermolecular interactions are crucial to cellular regulatory processes and are usually mediated by modular protein domains
Intramolecular interactions within the regulatory region center on the cSH2 domain, the only domain that interacts with the phospholipase C (PLC)-core
Further structural insights into the autoinhibitory surfaces provide a framework to interpret gain-of-function mutations in PLCg isoforms linked to immune disorders and illustrate a distinct mechanism for regulation of PLC activity by common interaction domains
Summary
Selective intermolecular interactions are crucial to cellular regulatory processes and are usually mediated by modular protein domains. Taking SH2 domains as an example, there is a notable difference in the number of structures reported for the isolated domains, free or bound to phosphotyrosine (pY)-containing polypeptide ligands, compared to larger structures of proteins encompassing or interacting with this domain (Liu et al, 2006) The importance of this more comprehensive information has been recently illustrated by the finding that the selectivity of fibroblast growth factor receptor (FGFR) is controlled by a secondary SH2 domain binding site, challenging the view that short, linear polypeptides can recapitulate the SH2 domain recognition of their native targets (Bae et al, 2009). Generation of comprehensive data regarding the organization and functions of the multidomain proteins is needed to further the understanding of the role of the diverse set of protein interaction domains and their specific modular function when integrated within larger polypeptides
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