PDBsum entry: 2rgn

Signaling protein complex

PDB id: 2rgn

Contents

Protein chains

324 a.a. *

327 a.a. *

177 a.a. *

168 a.a. *

Ligands

GDP-ALF ×2

Metals

_MG ×2

Waters ×6

* Residue conservation analysis

PDB id:

2rgn

Name:

Signaling protein complex

Title:

Crystal structure of p63rhogef complex with galpha-q and rho

Structure:

Guanine nucleotide-binding protein g(q) subunit a guanine nucleotide-binding protein g(i) subunit alpha-1. Chain: a, d. Fragment: chimeric protein of rat guanine nucleotide-bindin g(i) subunit alpha-1 n-terminal helix residues 1-28 and mo guanine nucleotide-binding protein g(q) subunit alpha resid 353. Synonym: guanine nucleotide-binding protein alpha-q. Engineered: yes.

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: gnaq. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Homo sapiens. Human. Organism_taxid: 9606.

Resolution:

3.50Å R-factor: 0.243 R-free: 0.299

Authors:

A.Shankaranarayanan,M.R.Nance,J.J.G.Tesmer

Key ref:

S.Lutz et al. (2007). Structure of Galphaq-p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs. Science, 318, 1923-1927. PubMed id: 18096806 DOI: 10.1126/science.1147554

Date:

04-Oct-07 Release date: 15-Jan-08

Protein chains

P21279  (GNAQ_MOUSE) -  Guanine nucleotide-binding protein G(q) subunit alpha

Seq: 359 a.a.

Struc: 324 a.a.*

Protein chains

Q86VW2  (ARHGP_HUMAN) -  Rho guanine nucleotide exchange factor 25

Seq: 580 a.a.

Struc: 327 a.a.

Protein chain

P61586  (RHOA_HUMAN) -  Transforming protein RhoA

Seq: 193 a.a.

Struc: 177 a.a.

Protein chain

P61586  (RHOA_HUMAN) -  Transforming protein RhoA

Seq: 193 a.a.

Struc: 168 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 

• Cellular component: intracellular (16 terms)
• Biological process: regulation of catenin import into nucleus (57 terms)
• Biochemical function: nucleotide binding (12 terms)

DOI no: 10.1126/science.1147554

Science 318:1923-1927 (2007)

PubMed id: 18096806

Structure of Galphaq-p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs.

S.Lutz, A.Shankaranarayanan, C.Coco, M.Ridilla, M.R.Nance, C.Vettel, D.Baltus, C.R.Evelyn, R.R.Neubig, T.Wieland, J.J.Tesmer.

ABSTRACT

The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric guanine nucleotide-binding protein (G protein) Galphaq and thereby links Galphaq-coupled receptors (GPCRs) to the activation of the small-molecular-weight G protein RhoA. We determined the crystal structure of the Galphaq-p63RhoGEF-RhoA complex, detailing the interactions of Galphaq with the Dbl and pleckstrin homology (DH and PH) domains of p63RhoGEF. These interactions involve the effector-binding site and the C-terminal region of Galphaq and appear to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio, Duet, and p63RhoGEF are shown to constitute a family of Galphaq effectors that appear to activate RhoA both in vitro and in intact cells. We propose that this structure represents the crux of an ancient signal transduction pathway that is expected to be important in an array of physiological processes.

Selected figure(s)

Figure 2.
Fig. 2. Crystal structure of the G [i/q]-p63RhoGEF-RhoA complex. (A) G [i/q] interacts with both the DH and PH domains of p63RhoGEF but not with RhoA. The complex is viewed from the perspective of the expected plane of the plasma membrane. N and C denote the most N- and C-terminal residues observed for each domain. Mg^2+·GDP·AlF[4]^– is shown as spheres. The three nucleotide-dependent conformational switches of G [i/q](SwI, SwII, and SwIII) are red. Two residues of the chimeric N terminus of G [i/q] are visible and extend toward the membrane surface, consistent with the N-terminal palmitoylation sites of G [q] engaging the lipid bilayer while it is in complex with p63RhoGEF. (B) Side view of the G [i/q]-p63RhoGEF-RhoA complex. The PH domain is modeled in its expected orientation at the plasma membrane (28), which as a consequence juxtaposes the C-terminal geranylgeranylation site of RhoA with the lipid bilayer.

Figure 4.
Fig. 4. Emerging themes for protein-protein interactions mediated by G [q] and PH domains and a model for p63RhoGEF activation by G [i/q]. (A) The p63RhoGEF PH domain in complex with G [i/q]. Inositol 1,4,5-trisphosphate (IP[3]) is modeled based on the phospholipase C– PH domain·IP[3] complex (29) to help define the expected plane of the lipid bilayer. (B) GRK2 binds similarly to the G [i/q]effector-binding site, using exposed hydrophobic residues in its 5 helix. Only the 5 and 6 helices of the GRK2 RH domain are shown. In both the p63RhoGEF and GRK2 complexes, G [i/q] is held in an orientation in which its longest axis is roughly parallel and switch I is held relatively close to the predicted membrane surface (top). In both complexes, the switch I region appears available for the simultaneous binding of regulator of G protein signaling proteins (30). (C) The GRK2 and p63RhoGEF PH domains engage their protein targets in a similar way, using a C-terminal helical extension and the loops at one edge of the β1-β4 sheet of the PH domain to form an extensive protein interaction site (Fig. 3). (D) The DH and PH domains of p63RhoGEF adopt a conformation distinct from that of Dbs (black). The view is the same as in Fig. 2A. The bridging interactions of G [i/q] (spheres) appear to rotate the position of the p63RhoGEF PH domain away from the RhoA binding site on the DH domain, along the plane of the membrane surface.

The above figures are reprinted by permission from the AAAs: Science (2007, 318, 1923-1927) copyright 2007.

Figures were selected by the author.