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

DOI: 10.1016/j.cell.2013.03.044 DOI Help
PMID: 23622247 PMID Help

Authors: Philippe Riou (King’s College London) , Svend Kjær (Cancer Research UK) , Ritu Garg (King’s College London) , Andy Purkiss (Cancer Research UK London Research Institute) , Roger George (Cancer Research UK) , Robert j. Cain (King’s College London) , Ganka Bineva (Cancer Research UK) , Nicolas Reymond (King’s College London) , Brad Mccoll (King’s College London) , Andrew Thompson (King’s College London) , Nicola O’reilly (Cancer Research UK London Research Institute) , Neil Mcdonald (Cancer Research UK London Research Institute) , Peter j. Parker (King’s College London) , Anne j. Ridley (King’s College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell , VOL 153 (3) , PAGES 640 - 653

State: Published (Approved)
Published: April 2013
Diamond Proposal Number(s): 8015

Open Access Open Access

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.

Journal Keywords: Amino; Animals; COS; Cell; Cercopithecus; Crystallography; X-Ray; Cytosol; Humans; Models; Molecular; Phosphorylation; Prenylation; Protein; rho GTP-Binding Proteins

Subject Areas: Chemistry

Instruments: I24-Microfocus Macromolecular Crystallography