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==Crystal structure of C42L cGMP dependent protein kinase I alpha (PKGI alpha) leucine zipper==
==Crystal structure of C42L cGMP dependent protein kinase I alpha (PKGI alpha) leucine zipper==
<StructureSection load='4r4m' size='340' side='right' caption='[[4r4m]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
<StructureSection load='4r4m' size='340' side='right'caption='[[4r4m]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4r4m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R4M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R4M FirstGlance]. <br>
<table><tr><td colspan='2'>[[4r4m]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R4M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R4M FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3nmd|3nmd]], [[1zxa|1zxa]], [[4ojk|4ojk]], [[4r4l|4r4l]]</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4r4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r4m OCA], [https://pdbe.org/4r4m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r4m RCSB], [https://www.ebi.ac.uk/pdbsum/4r4m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r4m ProSAT]</span></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PRKG1, PRKG1B, PRKGR1A, PRKGR1B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4r4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r4m OCA], [http://pdbe.org/4r4m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r4m RCSB], [http://www.ebi.ac.uk/pdbsum/4r4m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r4m ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/KGP1_HUMAN KGP1_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.<ref>PMID:8182057</ref> <ref>PMID:10567269</ref> <ref>PMID:11162591</ref> <ref>PMID:12082086</ref> <ref>PMID:11723116</ref> <ref>PMID:14608379</ref> <ref>PMID:15194681</ref> <ref>PMID:16990611</ref> <ref>PMID:21402151</ref>
[https://www.uniprot.org/uniprot/KGP1_HUMAN KGP1_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.<ref>PMID:8182057</ref> <ref>PMID:10567269</ref> <ref>PMID:11162591</ref> <ref>PMID:12082086</ref> <ref>PMID:11723116</ref> <ref>PMID:14608379</ref> <ref>PMID:15194681</ref> <ref>PMID:16990611</ref> <ref>PMID:21402151</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Guo, E]]
[[Category: Large Structures]]
[[Category: Kim, C]]
[[Category: Guo E]]
[[Category: Qin, L]]
[[Category: Kim C]]
[[Category: Reger, A S]]
[[Category: Qin L]]
[[Category: Yang, M P]]
[[Category: Reger AS]]
[[Category: Binding domain]]
[[Category: Yang MP]]
[[Category: Dna binding protein]]
[[Category: Kinase]]
[[Category: Leucine zipper]]
[[Category: Mypt1]]
[[Category: Rhoa]]

Revision as of 09:40, 2 March 2023

Crystal structure of C42L cGMP dependent protein kinase I alpha (PKGI alpha) leucine zipperCrystal structure of C42L cGMP dependent protein kinase I alpha (PKGI alpha) leucine zipper

Structural highlights

4r4m is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KGP1_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 PubMed

cGMP-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

  1. ↑ Butt E, Abel K, Krieger M, Palm D, Hoppe V, Hoppe J, Walter U. cAMP- and cGMP-dependent protein kinase phosphorylation sites of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) in vitro and in intact human platelets. J Biol Chem. 1994 May 20;269(20):14509-17. PMID:8182057
  2. ↑ Surks HK, Mochizuki N, Kasai Y, Georgescu SP, Tang KM, Ito M, Lincoln TM, Mendelsohn ME. Regulation of myosin phosphatase by a specific interaction with cGMP- dependent protein kinase Ialpha. Science. 1999 Nov 19;286(5444):1583-7. PMID:10567269
  3. ↑ Sawada N, Itoh H, Yamashita J, Doi K, Inoue M, Masatsugu K, Fukunaga Y, Sakaguchi S, Sone M, Yamahara K, Yurugi T, Nakao K. cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochem Biophys Res Commun. 2001 Jan 26;280(3):798-805. PMID:11162591 doi:10.1006/bbrc.2000.4194
  4. ↑ Casteel DE, Zhuang S, Gudi T, Tang J, Vuica M, Desiderio S, Pilz RB. cGMP-dependent protein kinase I beta physically and functionally interacts with the transcriptional regulator TFII-I. J Biol Chem. 2002 Aug 30;277(35):32003-14. Epub 2002 Jun 24. PMID:12082086 doi:10.1074/jbc.M112332200
  5. ↑ Rybalkin SD, Rybalkina IG, Feil R, Hofmann F, Beavo JA. Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in smooth muscle cells. J Biol Chem. 2002 Feb 1;277(5):3310-7. Epub 2001 Nov 26. PMID:11723116 doi:10.1074/jbc.M106562200
  6. ↑ Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y, Mendelsohn ME. Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med. 2003 Dec;9(12):1506-12. Epub 2003 Nov 9. PMID:14608379 doi:10.1038/nm958
  7. ↑ Wooldridge AA, MacDonald JA, Erdodi F, Ma C, Borman MA, Hartshorne DJ, Haystead TA. Smooth muscle phosphatase is regulated in vivo by exclusion of phosphorylation of threonine 696 of MYPT1 by phosphorylation of Serine 695 in response to cyclic nucleotides. J Biol Chem. 2004 Aug 13;279(33):34496-504. Epub 2004 Jun 11. PMID:15194681 doi:10.1074/jbc.M405957200
  8. ↑ Antl M, von Bruhl ML, Eiglsperger C, Werner M, Konrad I, Kocher T, Wilm M, Hofmann F, Massberg S, Schlossmann J. IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation. Blood. 2007 Jan 15;109(2):552-9. Epub 2006 Sep 21. PMID:16990611 doi:blood-2005-10-026294
  9. ↑ Yuasa K, Matsuda T, Tsuji A. Functional regulation of transient receptor potential canonical 7 by cGMP-dependent protein kinase Ialpha. Cell Signal. 2011 Jul;23(7):1179-87. doi: 10.1016/j.cellsig.2011.03.005. Epub, 2011 Mar 21. PMID:21402151 doi:10.1016/j.cellsig.2011.03.005
  10. ↑ Qin L, Reger AS, Guo E, Yang MP, Zwart P, Casteel DE, Kim C. Structures of cGMP-Dependent Protein Kinase (PKG) Ialpha Leucine Zippers Reveal an Interchain Disulfide Bond Important for Dimer Stability. Biochemistry. 2015 Jul 28;54(29):4419-22. doi: 10.1021/acs.biochem.5b00572. Epub , 2015 Jul 15. PMID:26132214 doi:http://dx.doi.org/10.1021/acs.biochem.5b00572

4r4m, resolution 1.92Å

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