14-3-3 Proteins Interact with a Hybrid Prenyl-phosphorylation Motif to Inhibit G Proteins

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Apr 30

PMID 23622247

Citations 63

Authors

Philippe Riou

Svend Kjaer

Ritu Garg

Andrew Purkiss

Roger George

Robert J Cain

Ganka Bineva

Nicolas Reymond

Brad McColl

Andrew J Thompson

Nicola OReilly

Neil Q McDonald

Peter J Parker

Anne J Ridley

Affiliations

Soon will be listed here.

Abstract

Signaling through G proteins normally involves conformational switching between GTP- and GDP-bound states. Several Rho GTPases are also regulated by RhoGDI binding and sequestering in the cytosol. Rnd proteins are atypical constitutively GTP-bound Rho proteins, whose regulation remains elusive. Here, we report a high-affinity 14-3-3-binding site at the C terminus of Rnd3 consisting of both the Cys241-farnesyl moiety and a Rho-associated coiled coil containing protein kinase (ROCK)-dependent Ser240 phosphorylation site. 14-3-3 binding to Rnd3 also involves phosphorylation of Ser218 by ROCK and/or Ser210 by protein kinase C (PKC). The crystal structure of a phosphorylated, farnesylated Rnd3 peptide with 14-3-3 reveals a hydrophobic groove in 14-3-3 proteins accommodating the farnesyl moiety. Functionally, 14-3-3 inhibits Rnd3-induced cell rounding by translocating it from the plasma membrane to the cytosol. Rnd1, Rnd2, and geranylgeranylated Rap1A interact similarly with 14-3-3. In contrast to the canonical GTP/GDP switch that regulates most Ras superfamily members, our results reveal an unprecedented mechanism for G protein inhibition by 14-3-3 proteins.

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