Structural and Functional Integration of the PLCγ Interaction Domains Critical for Regulatory Mechanisms and Signaling Deregulation

Summary

Multidomain 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.

Abstract

Graphical Abstract

Highlights

► Domains from PLCγ regulatory region show structural and functional integration ► Only cSH2 domain interacts with the PLC-core forming a high affinity surface ► Activation involves removal of autoinhibition and dissociation from the receptor ► Disease-linked mutations map to the autoinhibitory interface

Abstract

Structural studies of multi-domain proteins provide a considerable challenge due to the presence of flexible regions not amenable to crystallography. Bunney et al. describe a strategy that generated new insights into the structural organization and integration of individual domains comprising PLCγ.