3im4 | pdb_00003im4
Crystal structure of cAMP-dependent Protein Kinase A Regulatory Subunit I alpha in complex with dual-specific A-Kinase Anchoring Protein 2
Structural highlights
Disease[AKA10_HUMAN] Genetic variations in AKAP10 are a cause of susceptibility to sudden cardiac death (SCD) [MIM:115080]. Unexpected rapid natural death due to cardiovascular collapse within one hour of initial symptoms. It is usually caused by the worsening of existing heart diseases. The sudden onset of symptoms, such as chest pain and cardiac arrhythmias, particularly ventricular tachycardia, can lead to the loss of consciousness and cardiac arrest followed by biological death. Note=Increased susceptibility to sudden cardiac death may be conferred by AKAP10 variants that are associated with markers of low vagus nerve sensitivity, e.g. fast basal heart rate and low heart rate variability.[1] Function[KAP0_BOVIN] Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. [AKA10_HUMAN] Differentially targeted protein that binds to type I and II regulatory subunits of protein kinase A and anchors them to the mitochondria or the plasma membrane. Although the physiological relevance between PKA and AKAPS with mitochondria is not fully understood, one idea is that BAD, a proapoptotic member, is phosphorylated and inactivated by mitochondria-anchored PKA. It cannot be excluded too that it may facilitate PKA as well as G protein signal transduction, by acting as an adapter for assembling multiprotein complexes. With its RGS domain, it could lead to the interaction to G-alpha proteins, providing a link between the signaling machinery and the downstream kinase (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedA-kinase anchoring proteins (AKAPs) regulate cyclic AMP-dependent protein kinase (PKA) signaling in space and time. Dual-specific AKAP 2 (D-AKAP2) binds to the dimerization/docking (D/D) domain of both RI and RII regulatory subunits of PKA with high affinity. Here we have determined the structures of the RIalpha D/D domain alone and in complex with D-AKAP2. The D/D domain presents an extensive surface for binding through a well-formed N-terminal helix, and this surface restricts the diversity of AKAPs that can interact. The structures also underscore the importance of a redox-sensitive disulfide in affecting AKAP binding. An unexpected shift in the helical register of D-AKAP2 compared to the RIIalpha:D-AKAP2 complex structure makes the mode of binding to RIalpha novel. Finally, the comparison allows us to deduce a molecular explanation for the sequence and spatial determinants of AKAP specificity. Structure of D-AKAP2:PKA RI complex: insights into AKAP specificity and selectivity.,Sarma GN, Kinderman FS, Kim C, von Daake S, Chen L, Wang BC, Taylor SS Structure. 2010 Feb 10;18(2):155-66. PMID:20159461[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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