14-3-3 Proteins Interact with a Hybrid Prenyl-Phosphorylation Motif to Inhibit G Proteins
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ICR Authors
Authors
Riou, P
Kjær, S
Garg, R
Purkiss, A
George, R
Cain, RJ
Bineva, G
Reymond, N
McColl, B
Thompson, AJ
O’Reilly, N
McDonald, NQ
Parker, PJ
Ridley, AJ
Kjær, S
Garg, R
Purkiss, A
George, R
Cain, RJ
Bineva, G
Reymond, N
McColl, B
Thompson, AJ
O’Reilly, N
McDonald, NQ
Parker, PJ
Ridley, AJ
Document Type
Journal Article
Date
2013-04-01
Date Accepted
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.
Citation
CELL, 2013, 153 (3), pp. 640 - 653
DOI
Source Title
Publisher
Elsevier BV
ISSN
0092-8674