Determinants at the N- and C-termini of G[alpha]12 required for activation of Rho-mediated signaling
Doc number: 3 Abstract Background: Heterotrimeric guanine nucleotide binding proteins of the G12/13 subfamily, which includes the α-subunits Gα12 and Gα13 , stimulate the monomeric G protein RhoA through interaction with a distinct subset of Rho-specific guanine nucleotide exchange factors (RhoGEFs)...
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Published in | Journal of molecular signaling Vol. 8 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Ubiquity Press
01.01.2013
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Subjects | |
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Abstract | Doc number: 3 Abstract Background: Heterotrimeric guanine nucleotide binding proteins of the G12/13 subfamily, which includes the α-subunits Gα12 and Gα13 , stimulate the monomeric G protein RhoA through interaction with a distinct subset of Rho-specific guanine nucleotide exchange factors (RhoGEFs). The structural features that mediate interaction between Gα13 and RhoGEFs have been examined in crystallographic studies of the purified complex, whereas a Gα12 :RhoGEF complex has not been reported. Several signaling responses and effector interactions appear unique to Gα12 or Gα13 , despite their similarity in amino acid sequence. Methods: To comprehensively examine Gα12 for regions involved in RhoGEF interaction, we screened a panel of Gα12 cassette substitution mutants for binding to leukemia-associated RhoGEF (LARG) and for activation of serum response element mediated transcription. Results: We identified several cassette substitutions that disrupt Gα12 binding to LARG and the related p115RhoGEF. These Gα12 mutants also were impaired in activating serum response element mediated signaling, a Rho-dependent response. Most of these mutants matched corresponding regions of Gα13 reported to contact p115RhoGEF, but unexpectedly, several RhoGEF-uncoupling mutations were found within the N- and C-terminal regions of Gα12 . Trypsin protection assays revealed several mutants in these regions as retaining conformational activation. In addition, charge substitutions near the Gα12 N-terminus selectively disrupted binding to LARG but not p115RhoGEF. Conclusions: Several structural aspects of the Gα12 :RhoGEF interface differ from the reported Gα13 :RhoGEF complex, particularly determinants within the C-terminal α5 helix and structurally uncharacterized N-terminus of Gα12 . Furthermore, key residues at the Gα12 N-terminus may confer selectivity for LARG as a downstream effector. |
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AbstractList | Doc number: 3 Abstract Background: Heterotrimeric guanine nucleotide binding proteins of the G12/13 subfamily, which includes the α-subunits Gα12 and Gα13 , stimulate the monomeric G protein RhoA through interaction with a distinct subset of Rho-specific guanine nucleotide exchange factors (RhoGEFs). The structural features that mediate interaction between Gα13 and RhoGEFs have been examined in crystallographic studies of the purified complex, whereas a Gα12 :RhoGEF complex has not been reported. Several signaling responses and effector interactions appear unique to Gα12 or Gα13 , despite their similarity in amino acid sequence. Methods: To comprehensively examine Gα12 for regions involved in RhoGEF interaction, we screened a panel of Gα12 cassette substitution mutants for binding to leukemia-associated RhoGEF (LARG) and for activation of serum response element mediated transcription. Results: We identified several cassette substitutions that disrupt Gα12 binding to LARG and the related p115RhoGEF. These Gα12 mutants also were impaired in activating serum response element mediated signaling, a Rho-dependent response. Most of these mutants matched corresponding regions of Gα13 reported to contact p115RhoGEF, but unexpectedly, several RhoGEF-uncoupling mutations were found within the N- and C-terminal regions of Gα12 . Trypsin protection assays revealed several mutants in these regions as retaining conformational activation. In addition, charge substitutions near the Gα12 N-terminus selectively disrupted binding to LARG but not p115RhoGEF. Conclusions: Several structural aspects of the Gα12 :RhoGEF interface differ from the reported Gα13 :RhoGEF complex, particularly determinants within the C-terminal α5 helix and structurally uncharacterized N-terminus of Gα12 . Furthermore, key residues at the Gα12 N-terminus may confer selectivity for LARG as a downstream effector. |
Author | Fisher, Elizabeth S Smolski, William C Olson, Calla M Foster, Lori A Meigs, Thomas E Choi, Tina Y Montgomery, Ellyn R Ritchie, Benjamin J |
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Copyright | 2013 Ritchie et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
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Snippet | Doc number: 3 Abstract Background: Heterotrimeric guanine nucleotide binding proteins of the G12/13 subfamily, which includes the α-subunits Gα12 and Gα13 ,... |
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Title | Determinants at the N- and C-termini of G[alpha]12 required for activation of Rho-mediated signaling |
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