Structural design principles that underlie the multi-specific interactions of Gα q with dissimilar partners

Shir Navot, Mickey Kosloff

Research output: Contribution to journalArticlepeer-review


q is a ubiquitous molecular switch that activates the effectors phospholipase-C-β3 (PLC-β3) and Rho guanine-nucleotide exchange factors. Gα q is inactivated by regulators of G protein signaling proteins, as well as by PLC-β3. Gα q further interacts with G protein-coupled receptor kinase 2 (GRK2), although the functional role of this interaction is debated. While X-ray structures of Gα q bound to representatives of these partners have revealed details of their interactions, the mechanistic basis for differential Gα q interactions with multiple partners (i.e., Gα q multi-specificity) has not been elucidated at the individual residue resolution. Here, we map the structural determinants of Gα q multi-specificity using structure-based energy calculations. We delineate regions that specifically interact with GTPase Activating Proteins (GAPs) and residues that exclusively contribute to effector interactions, showing that only the Gα q “Switch II” region interacts with all partners. Our analysis further suggests that Gα q -GRK2 interactions are consistent with GRK2 functioning as an effector, rather than a GAP. Our multi-specificity analysis pinpoints Gα q residues that uniquely contribute to interactions with particular partners, enabling precise manipulation of these cascades. As such, we dissect the molecular basis of Gα q function as a central signaling hub, which can be used to target Gα q -mediated signaling in therapeutic interventions.

Original languageEnglish
Article number6898
Pages (from-to)1-10
JournalScientific Reports
Issue number1
StatePublished - 1 Dec 2019

Bibliographical note

Funding Information:
This work was supported by the Israel Science Foundation (grants 1454/13, 1959/13 and 2155/15).

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Structural design principles that underlie the multi-specific interactions of Gα q with dissimilar partners'. Together they form a unique fingerprint.

Cite this