2lg1

Solution structure of the human AKAP13 PH domain and stabilizing DH helix

spinqualitylabelsall models 2lg1 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2lg1 is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AKP13_HUMAN Anchors cAMP-dependent protein kinase (PKA) and acts as an adapter protein to selectively couple G alpha-13 and Rho. Augments gene activation by the estrogen receptor in an element-specific and ligand-dependent manner. Activates estrogen receptor beta by a p38 MAPK-dependent pathway. Stimulates exchange activity on Rho proteins in vitro, but not on CDC42, Ras or Rac and may bind calcium ions. Publication Abstract from PubMed The small GTPase RhoA promotes deregulated signalling upon interaction with Lbc, the oncogenic form of A-kinase anchoring protein (AKAP). The onco-Lbc protein is a hyperactive Rho-specific guanine nucleotide exchange factor (GEF), but its structural mechanism has not been reported, despite its involvement in cardiac hypertrophy and cancer causation. The pleckstrin homology (PH) domain of Lbc is located at the C-terminal end of the protein, and is shown here to specifically recognize activated RhoA rather than lipids. The isolated dbl homology (DH) domain can function as an independent activator with an enhanced activity. However, the DH domain normally does not act as a solitary Lbc interface with RhoA-GDP. Instead it is negatively controlled by the PH domain. In particular the DH helical bundle is coupled to the structurally dependent PH domain through a helical linker, which reduces its activity. Together the two domains form a rigid scaffold in solution, as evidenced by small angle X-ray scattering and 1H,13C,15N-based NMR spectroscopy. The two domains assume a "chair" shape, with its back possessing independent GEF activity, and the PH domain providing a broad seat for RhoA-GTP docking rather than membrane recognition. This provides structural and dynamical insights into how DH and PH domains work together in solution to support regulated RhoA activity. Mutational analysis supports the bifunctional PH domain mediation of DH:RhoA interactions and explains why the tandem domain is required for controlled GEF signaling. Structural Insights into the Activation of the RhoA GTPase by the Lbc Oncoprotein.,Lenoir M, Sugawara M, Kaur J, Ball LJ, Overduin M J Biol Chem. 2014 Jul 3. pii: jbc.M114.561787. PMID:24993829 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also A-kinase anchor protein 3D structures

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