4r4m | pdb_00004r4m
Crystal structure of C42L cGMP dependent protein kinase I alpha (PKGI alpha) leucine zipper
Structural highlights
FunctionKGP1_HUMAN Serine/threonine protein kinase that acts as key mediator of the nitric oxide (NO)/cGMP signaling pathway. GMP binding activates PRKG1, which phosphorylates serines and threonines on many cellular proteins. Numerous protein targets for PRKG1 phosphorylation are implicated in modulating cellular calcium, but the contribution of each of these targets may vary substantially among cell types. Proteins that are phosphorylated by PRKG1 regulate platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes involved in several aspects of the CNS like axon guidance, hippocampal and cerebellar learning, circadian rhythm and nociception. Smooth muscle relaxation is mediated through lowering of intracellular free calcium, by desensitization of contractile proteins to calcium, and by decrease in the contractile state of smooth muscle or in platelet activation. Regulates intracellular calcium levels via several pathways: phosphorylates MRVI1/IRAG and inhibits IP3-induced Ca(2+) release from intracellular stores, phosphorylation of KCNMA1 (BKCa) channels decreases intracellular Ca(2+) levels, which leads to increased opening of this channel. PRKG1 phosphorylates the canonical transient receptor potential channel (TRPC) family which inactivates the associated inward calcium current. Another mode of action of NO/cGMP/PKGI signaling involves PKGI-mediated inactivation of the Ras homolog gene family member A (RhoA). Phosphorylation of RHOA by PRKG1 blocks the action of this protein in myriad processes: regulation of RHOA translocation; decreasing contraction; controlling vesicle trafficking, reduction of myosin light chain phosphorylation resulting in vasorelaxation. Activation of PRKG1 by NO signaling alters also gene expression in a number of tissues. In smooth muscle cells, increased cGMP and PRKG1 activity influence expression of smooth muscle-specific contractile proteins, levels of proteins in the NO/cGMP signaling pathway, down-regulation of the matrix proteins osteopontin and thrombospondin-1 to limit smooth muscle cell migration and phenotype. Regulates vasodilator-stimulated phosphoprotein (VASP) functions in platelets and smooth muscle.[1] [2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedcGMP-dependent protein kinase (PKG) Ialpha is a central regulator of smooth muscle tone and vasorelaxation. The N-terminal leucine zipper (LZ) domain dimerizes and targets PKG Ialpha by interacting with G-kinase-anchoring proteins. The PKG Ialpha LZ contains C42 that is known to form a disulfide bond upon oxidation and to activate PKG Ialpha. To understand the molecular details of the PKG Ialpha LZ and C42-C42' disulfide bond, we determined crystal structures of the PKG Ialpha wild-type (WT) LZ and C42L LZ. Our data demonstrate that the C42-C42' disulfide bond dramatically stabilizes PKG Ialpha and that the C42L mutant mimics the oxidized WT LZ structurally. Structures of cGMP-Dependent Protein Kinase (PKG) Ialpha Leucine Zippers Reveal an Interchain Disulfide Bond Important for Dimer Stability.,Qin L, Reger AS, Guo E, Yang MP, Zwart P, Casteel DE, Kim C Biochemistry. 2015 Jul 28;54(29):4419-22. doi: 10.1021/acs.biochem.5b00572. Epub , 2015 Jul 15. PMID:26132214[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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