4d0o

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AKAP13 (AKAP-Lbc) DH domainAKAP13 (AKAP-Lbc) DH domain

Structural highlights

4d0o is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.75Å
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.[1] [2] [3] [4]

Publication Abstract from PubMed

The RhoGEF domain of AKAP-Lbc (AKAP13) catalyses nucleotide exchange on RhoA and is involved in development of cardiac hypertrophy. The RhoGEF activity of AKAP-Lbc has also been implicated in cancer. We have determined the X-ray crystal structure of the complex between RhoA:GDP and the AKAP-Lbc RhoGEF (DH-PH) domain to 2.1 A resolution. The structure reveals important differences compared to related RhoGEF proteins such as Leukemia-associated RhoGEF. Nucleotide exchange assays comparing the activity of the DH-PH domain to the DH domain alone showed no role for the PH domain in nucleotide exchange, which is explained by the RhoA:AKAP-Lbc structure. Comparison to a structure of the isolated AKAP-Lbc DH domain revealed a change in conformation of the N-terminal 'GEF switch' region upon binding to RhoA. Isothermal titration calorimetry showed that AKAP-Lbc has only micromolar affinity for RhoA which combined with the presence of potential binding pockets for small molecules on AKAP-Lbc raises the possibility of targeting AKAP-Lbc with guanine nucleotide exchange factor inhibitors.

The Crystal Structure of the RhoA : AKAP-Lbc DH-PH Domain Complex.,Abdul Azeez KR, Knapp S, Fernandes JM, Klussmann E, Elkins JM Biochem J. 2014 Sep 4. PMID:25186459[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Diviani D, Soderling J, Scott JD. AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation. J Biol Chem. 2001 Nov 23;276(47):44247-57. Epub 2001 Sep 6. PMID:11546812 doi:http://dx.doi.org/10.1074/jbc.M106629200
  2. ↑ Rubino D, Driggers P, Arbit D, Kemp L, Miller B, Coso O, Pagliai K, Gray K, Gutkind S, Segars J. Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action. Oncogene. 1998 May 14;16(19):2513-26. PMID:9627117 doi:http://dx.doi.org/10.1038/sj.onc.1201783
  3. ↑ Sterpetti P, Hack AA, Bashar MP, Park B, Cheng SD, Knoll JH, Urano T, Feig LA, Toksoz D. Activation of the Lbc Rho exchange factor proto-oncogene by truncation of an extended C terminus that regulates transformation and targeting. Mol Cell Biol. 1999 Feb;19(2):1334-45. PMID:9891067
  4. ↑ Driggers PH, Segars JH, Rubino DM. The proto-oncoprotein Brx activates estrogen receptor beta by a p38 mitogen-activated protein kinase pathway. J Biol Chem. 2001 Dec 14;276(50):46792-7. Epub 2001 Sep 28. PMID:11579095 doi:http://dx.doi.org/10.1074/jbc.M106927200
  5. ↑ Abdul Azeez KR, Knapp S, Fernandes JM, Klussmann E, Elkins JM. The Crystal Structure of the RhoA : AKAP-Lbc DH-PH Domain Complex. Biochem J. 2014 Sep 4. PMID:25186459 doi:http://dx.doi.org/10.1042/BJ20140606

4d0o, resolution 2.75Å

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