6pjx

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of G Protein-Coupled Receptor Kinase 5 (GRK5) in Complex with Calmodulin (CaM)

Structural highlights

6pjx is a 2 chain structure with sequence from Homo sapiens and Podiceps cristatus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.96Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GRK5_HUMAN Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

The phosphorylation of G protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) facilitates arrestin binding and receptor desensitization. Although this process can be regulated by Ca(2+)-binding proteins such as calmodulin (CaM) and recoverin, the molecular mechanisms are poorly understood. Here, we report structural, computational, and biochemical analysis of a CaM complex with GRK5, revealing how CaM shapes GRK5 response to calcium. The CaM N and C domains bind independently to two helical regions at the GRK5 N and C termini to inhibit GPCR phosphorylation, though only the C domain interaction disrupts GRK5 membrane association, thereby facilitating cytoplasmic translocation. The CaM N domain strongly activates GRK5 via ordering of the amphipathic alphaN-helix of GRK5 and allosteric disruption of kinase-RH domain interaction for phosphorylation of cytoplasmic GRK5 substrates. These results provide a framework for understanding how two functional effects, GRK5 activation and localization, can cooperate under control of CaM for selective substrate targeting by GRK5.

Structure of a GRK5-Calmodulin Complex Reveals Molecular Mechanism of GRK Activation and Substrate Targeting.,Komolov KE, Sulon SM, Bhardwaj A, van Keulen SC, Duc NM, Laurinavichyute DK, Lou HJ, Turk BE, Chung KY, Dror RO, Benovic JL Mol Cell. 2021 Jan 21;81(2):323-339.e11. doi: 10.1016/j.molcel.2020.11.026. Epub , 2020 Dec 14. PMID:33321095^[6]

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

References

↑ Barthet G, Carrat G, Cassier E, Barker B, Gaven F, Pillot M, Framery B, Pellissier LP, Augier J, Kang DS, Claeysen S, Reiter E, Baneres JL, Benovic JL, Marin P, Bockaert J, Dumuis A. Beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling. EMBO J. 2009 Sep 16;28(18):2706-18. Epub 2009 Aug 6. PMID:19661922 doi:http://dx.doi.org/emboj2009215
↑ Chen M, Philipp M, Wang J, Premont RT, Garrison TR, Caron MG, Lefkowitz RJ, Chen W. G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. J Biol Chem. 2009 Dec 11;284(50):35040-8. doi: 10.1074/jbc.M109.047456. Epub 2009, Oct 2. PMID:19801552 doi:10.1074/jbc.M109.047456
↑ Baameur F, Morgan DH, Yao H, Tran TM, Hammitt RA, Sabui S, McMurray JS, Lichtarge O, Clark RB. Role for the regulator of G-protein signaling homology domain of G protein-coupled receptor kinases 5 and 6 in beta 2-adrenergic receptor and rhodopsin phosphorylation. Mol Pharmacol. 2010 Mar;77(3):405-15. doi: 10.1124/mol.109.058115. Epub 2009 Dec , 28. PMID:20038610 doi:http://dx.doi.org/10.1124/mol.109.058115
↑ Chen X, Zhu H, Yuan M, Fu J, Zhou Y, Ma L. G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis. J Biol Chem. 2010 Apr 23;285(17):12823-30. doi: 10.1074/jbc.M109.094243. Epub, 2010 Feb 2. PMID:20124405 doi:http://dx.doi.org/10.1074/jbc.M109.094243
↑ Barker BL, Benovic JL. G protein-coupled receptor kinase 5 phosphorylation of hip regulates internalization of the chemokine receptor CXCR4. Biochemistry. 2011 Aug 16;50(32):6933-41. doi: 10.1021/bi2005202. Epub 2011 Jul, 12. PMID:21728385 doi:http://dx.doi.org/10.1021/bi2005202
↑ Komolov KE, Sulon SM, Bhardwaj A, van Keulen SC, Duc NM, Laurinavichyute DK, Lou HJ, Turk BE, Chung KY, Dror RO, Benovic JL. Structure of a GRK5-Calmodulin Complex Reveals Molecular Mechanism of GRK Activation and Substrate Targeting. Mol Cell. 2021 Jan 21;81(2):323-339.e11. PMID:33321095 doi:10.1016/j.molcel.2020.11.026

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6pjx"

@@ Line 1: / Line 1: @@
-====
+==Crystal Structure of G Protein-Coupled Receptor Kinase 5 (GRK5) in Complex with Calmodulin (CaM)==
-<StructureSection load='6pjx' size='340' side='right'caption='[[6pjx]]' scene=''>
+<StructureSection load='6pjx' size='340' side='right'caption='[[6pjx]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6pjx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Podiceps_cristatus Podiceps cristatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PJX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PJX FirstGlance]. <br>
-</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=6pjx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pjx OCA], [https://pdbe.org/6pjx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pjx RCSB], [https://www.ebi.ac.uk/pdbsum/6pjx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pjx ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.96&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SGV:SANGIVAMYCIN'>SGV</scene></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=6pjx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pjx OCA], [https://pdbe.org/6pjx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pjx RCSB], [https://www.ebi.ac.uk/pdbsum/6pjx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pjx ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/GRK5_HUMAN GRK5_HUMAN] Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro).<ref>PMID:19661922</ref> <ref>PMID:19801552</ref> <ref>PMID:20038610</ref> <ref>PMID:20124405</ref> <ref>PMID:21728385</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The phosphorylation of G protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) facilitates arrestin binding and receptor desensitization. Although this process can be regulated by Ca(2+)-binding proteins such as calmodulin (CaM) and recoverin, the molecular mechanisms are poorly understood. Here, we report structural, computational, and biochemical analysis of a CaM complex with GRK5, revealing how CaM shapes GRK5 response to calcium. The CaM N and C domains bind independently to two helical regions at the GRK5 N and C termini to inhibit GPCR phosphorylation, though only the C domain interaction disrupts GRK5 membrane association, thereby facilitating cytoplasmic translocation. The CaM N domain strongly activates GRK5 via ordering of the amphipathic alphaN-helix of GRK5 and allosteric disruption of kinase-RH domain interaction for phosphorylation of cytoplasmic GRK5 substrates. These results provide a framework for understanding how two functional effects, GRK5 activation and localization, can cooperate under control of CaM for selective substrate targeting by GRK5.
+Structure of a GRK5-Calmodulin Complex Reveals Molecular Mechanism of GRK Activation and Substrate Targeting.,Komolov KE, Sulon SM, Bhardwaj A, van Keulen SC, Duc NM, Laurinavichyute DK, Lou HJ, Turk BE, Chung KY, Dror RO, Benovic JL Mol Cell. 2021 Jan 21;81(2):323-339.e11. doi: 10.1016/j.molcel.2020.11.026. Epub , 2020 Dec 14. PMID:33321095<ref>PMID:33321095</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6pjx" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Calmodulin 3D structures|Calmodulin 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Z-disk]]
+[[Category: Podiceps cristatus]]
+[[Category: Benovic JL]]
+[[Category: Bhardwaj A]]
+[[Category: Komolov KE]]
+[[Category: Sulon S]]

6pjx

From Proteopedia

Current revision

Crystal Structure of G Protein-Coupled Receptor Kinase 5 (GRK5) in Complex with Calmodulin (CaM)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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