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==Crystal structure of Casein Kinase I delta (CK1d) with alphaG-in conformation==
==Crystal structure of Casein Kinase I delta (CK1d) with alphaG-in conformation==
<StructureSection load='7p7h' size='340' side='right'caption='[[7p7h]]' scene=''>
<StructureSection load='7p7h' size='340' side='right'caption='[[7p7h]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7P7H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P7H FirstGlance]. <br>
<table><tr><td colspan='2'>[[7p7h]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7P7H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P7H 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=7p7h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p7h OCA], [https://pdbe.org/7p7h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p7h RCSB], [https://www.ebi.ac.uk/pdbsum/7p7h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p7h ProSAT]</span></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</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=7p7h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p7h OCA], [https://pdbe.org/7p7h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p7h RCSB], [https://www.ebi.ac.uk/pdbsum/7p7h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p7h ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/KC1D_HUMAN KC1D_HUMAN]] Familial advanced sleep-phase syndrome. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[[https://www.uniprot.org/uniprot/KC1D_HUMAN KC1D_HUMAN]] Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. May act as a negative regulator of circadian rhythmicity by phosphorylating PER1 and PER2, leading to retain PER1 in the cytoplasm. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate.<ref>PMID:10606744</ref> <ref>PMID:12270943</ref> <ref>PMID:14761950</ref> <ref>PMID:16027726</ref> <ref>PMID:17962809</ref> <ref>PMID:17562708</ref> <ref>PMID:19043076</ref> <ref>PMID:19339517</ref> <ref>PMID:20637175</ref> <ref>PMID:20041275</ref> <ref>PMID:20048001</ref> <ref>PMID:20699359</ref> <ref>PMID:20696890</ref> <ref>PMID:20407760</ref> <ref>PMID:21084295</ref> <ref>PMID:21422228</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
CK1s are acidophilic serine/threonine kinases with multiple critical cellular functions; their misregulation contributes to cancer, neurodegenerative diseases, and sleep phase disorders. Here, we describe an evolutionarily conserved mechanism of CK1 activity: autophosphorylation of a threonine (T220 in human CK1delta) located at the N terminus of helix alphaG, proximal to the substrate binding cleft. Crystal structures and molecular dynamics simulations uncovered inherent plasticity in alphaG that increased upon T220 autophosphorylation. The phosphorylation-induced structural changes significantly altered the conformation of the substrate binding cleft, affecting substrate specificity. In T220 phosphorylated yeast and human CK1s, activity toward many substrates was decreased, but we also identified a high-affinity substrate that was phosphorylated more rapidly, and quantitative phosphoproteomics revealed that disrupting T220 autophosphorylation rewired CK1 signaling in Schizosaccharomyces pombe. T220 is present exclusively in the CK1 family, thus its autophosphorylation may have evolved as a unique regulatory mechanism for this important family.
Kinase domain autophosphorylation rewires the activity and substrate specificity of CK1 enzymes.,Cullati SN, Chaikuad A, Chen JS, Gebel J, Tesmer L, Zhubi R, Navarrete-Perea J, Guillen RX, Gygi SP, Hummer G, Dotsch V, Knapp S, Gould KL Mol Cell. 2022 Mar 21. pii: S1097-2765(22)00214-3. doi:, 10.1016/j.molcel.2022.03.005. PMID:35353987<ref>PMID:35353987</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7p7h" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Chaikuad A]]
[[Category: Chaikuad, A]]
[[Category: Knapp S]]
[[Category: Knapp, S]]
[[Category: Zhubi R]]
[[Category: Structural genomic]]
[[Category: Zhubi, R]]
[[Category: Activation segment]]
[[Category: Alpha g]]
[[Category: Casein kinase]]
[[Category: Ck1d]]
[[Category: Conformation plasticity]]
[[Category: Csnk1d]]
[[Category: Sgc]]
[[Category: Transferase]]

Revision as of 06:07, 21 April 2022

Crystal structure of Casein Kinase I delta (CK1d) with alphaG-in conformationCrystal structure of Casein Kinase I delta (CK1d) with alphaG-in conformation

Structural highlights

7p7h is a 2 chain structure. 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

Disease

[KC1D_HUMAN] Familial advanced sleep-phase syndrome. The disease is caused by mutations affecting the gene represented in this entry.

Function

[KC1D_HUMAN] Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. May act as a negative regulator of circadian rhythmicity by phosphorylating PER1 and PER2, leading to retain PER1 in the cytoplasm. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]

Publication Abstract from PubMed

CK1s are acidophilic serine/threonine kinases with multiple critical cellular functions; their misregulation contributes to cancer, neurodegenerative diseases, and sleep phase disorders. Here, we describe an evolutionarily conserved mechanism of CK1 activity: autophosphorylation of a threonine (T220 in human CK1delta) located at the N terminus of helix alphaG, proximal to the substrate binding cleft. Crystal structures and molecular dynamics simulations uncovered inherent plasticity in alphaG that increased upon T220 autophosphorylation. The phosphorylation-induced structural changes significantly altered the conformation of the substrate binding cleft, affecting substrate specificity. In T220 phosphorylated yeast and human CK1s, activity toward many substrates was decreased, but we also identified a high-affinity substrate that was phosphorylated more rapidly, and quantitative phosphoproteomics revealed that disrupting T220 autophosphorylation rewired CK1 signaling in Schizosaccharomyces pombe. T220 is present exclusively in the CK1 family, thus its autophosphorylation may have evolved as a unique regulatory mechanism for this important family.

Kinase domain autophosphorylation rewires the activity and substrate specificity of CK1 enzymes.,Cullati SN, Chaikuad A, Chen JS, Gebel J, Tesmer L, Zhubi R, Navarrete-Perea J, Guillen RX, Gygi SP, Hummer G, Dotsch V, Knapp S, Gould KL Mol Cell. 2022 Mar 21. pii: S1097-2765(22)00214-3. doi:, 10.1016/j.molcel.2022.03.005. PMID:35353987[17]

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

References

  1. ↑ Dumaz N, Milne DM, Meek DW. Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. FEBS Lett. 1999 Dec 17;463(3):312-6. PMID:10606744
  2. ↑ Cooper CD, Lampe PD. Casein kinase 1 regulates connexin-43 gap junction assembly. J Biol Chem. 2002 Nov 22;277(47):44962-8. Epub 2002 Sep 20. PMID:12270943 doi:10.1074/jbc.M209427200
  3. ↑ Li G, Yin H, Kuret J. Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. J Biol Chem. 2004 Apr 16;279(16):15938-45. Epub 2004 Feb 2. PMID:14761950 doi:10.1074/jbc.M314116200
  4. ↑ Stoter M, Bamberger AM, Aslan B, Kurth M, Speidel D, Loning T, Frank HG, Kaufmann P, Lohler J, Henne-Bruns D, Deppert W, Knippschild U. Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. Oncogene. 2005 Dec 1;24(54):7964-75. PMID:16027726 doi:10.1038/sj.onc.1208941
  5. ↑ von Blume J, Knippschild U, Dequiedt F, Giamas G, Beck A, Auer A, Van Lint J, Adler G, Seufferlein T. Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2. EMBO J. 2007 Nov 14;26(22):4619-33. Epub 2007 Oct 25. PMID:17962809 doi:10.1038/sj.emboj.7601891
  6. ↑ Hanger DP, Byers HL, Wray S, Leung KY, Saxton MJ, Seereeram A, Reynolds CH, Ward MA, Anderton BH. Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem. 2007 Aug 10;282(32):23645-54. Epub 2007 Jun 11. PMID:17562708 doi:10.1074/jbc.M703269200
  7. ↑ Grozav AG, Chikamori K, Kozuki T, Grabowski DR, Bukowski RM, Willard B, Kinter M, Andersen AH, Ganapathi R, Ganapathi MK. Casein kinase I delta/epsilon phosphorylates topoisomerase IIalpha at serine-1106 and modulates DNA cleavage activity. Nucleic Acids Res. 2009 Feb;37(2):382-92. doi: 10.1093/nar/gkn934. Epub 2008 Nov , 29. PMID:19043076 doi:10.1093/nar/gkn934
  8. ↑ Giamas G, Castellano L, Feng Q, Knippschild U, Jacob J, Thomas RS, Coombes RC, Smith CL, Jiao LR, Stebbing J. CK1delta modulates the transcriptional activity of ERalpha via AIB1 in an estrogen-dependent manner and regulates ERalpha-AIB1 interactions. Nucleic Acids Res. 2009 May;37(9):3110-23. doi: 10.1093/nar/gkp136. Epub 2009 Apr, 1. PMID:19339517 doi:10.1093/nar/gkp136
  9. ↑ Smal C, Vertommen D, Amsailale R, Arts A, Degand H, Morsomme P, Rider MH, Neste EV, Bontemps F. Casein kinase 1delta activates human recombinant deoxycytidine kinase by Ser-74 phosphorylation, but is not involved in the in vivo regulation of its activity. Arch Biochem Biophys. 2010 Oct 1;502(1):44-52. doi: 10.1016/j.abb.2010.07.009., Epub 2010 Jul 14. PMID:20637175 doi:10.1016/j.abb.2010.07.009
  10. ↑ Venerando A, Marin O, Cozza G, Bustos VH, Sarno S, Pinna LA. Isoform specific phosphorylation of p53 by protein kinase CK1. Cell Mol Life Sci. 2010 Apr;67(7):1105-18. doi: 10.1007/s00018-009-0236-7. Epub, 2009 Dec 30. PMID:20041275 doi:10.1007/s00018-009-0236-7
  11. ↑ Zhao B, Li L, Tumaneng K, Wang CY, Guan KL. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. 2010 Jan 1;24(1):72-85. doi: 10.1101/gad.1843810. PMID:20048001 doi:10.1101/gad.1843810
  12. ↑ Kalousi A, Mylonis I, Politou AS, Chachami G, Paraskeva E, Simos G. Casein kinase 1 regulates human hypoxia-inducible factor HIF-1. J Cell Sci. 2010 Sep 1;123(Pt 17):2976-86. doi: 10.1242/jcs.068122. Epub 2010 Aug, 10. PMID:20699359 doi:10.1242/jcs.068122
  13. ↑ Meng QJ, Maywood ES, Bechtold DA, Lu WQ, Li J, Gibbs JE, Dupre SM, Chesham JE, Rajamohan F, Knafels J, Sneed B, Zawadzke LE, Ohren JF, Walton KM, Wager TT, Hastings MH, Loudon AS. Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5. doi:, 10.1073/pnas.1005101107. Epub 2010 Aug 9. PMID:20696890 doi:10.1073/pnas.1005101107
  14. ↑ Sprouse J, Reynolds L, Kleiman R, Tate B, Swanson TA, Pickard GE. Chronic treatment with a selective inhibitor of casein kinase I delta/epsilon yields cumulative phase delays in circadian rhythms. Psychopharmacology (Berl). 2010 Jul;210(4):569-76. doi:, 10.1007/s00213-010-1860-5. Epub 2010 Apr 21. PMID:20407760 doi:10.1007/s00213-010-1860-5
  15. ↑ Biswas A, Mukherjee S, Das S, Shields D, Chow CW, Maitra U. Opposing action of casein kinase 1 and calcineurin in nucleo-cytoplasmic shuttling of mammalian translation initiation factor eIF6. J Biol Chem. 2011 Jan 28;286(4):3129-38. doi: 10.1074/jbc.M110.188565. Epub 2010 , Nov 17. PMID:21084295 doi:10.1074/jbc.M110.188565
  16. ↑ Greer YE, Rubin JS. Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. J Cell Biol. 2011 Mar 21;192(6):993-1004. doi: 10.1083/jcb.201011111. PMID:21422228 doi:10.1083/jcb.201011111
  17. ↑ Cullati SN, Chaikuad A, Chen JS, Gebel J, Tesmer L, Zhubi R, Navarrete-Perea J, Guillen RX, Gygi SP, Hummer G, Dotsch V, Knapp S, Gould KL. Kinase domain autophosphorylation rewires the activity and substrate specificity of CK1 enzymes. Mol Cell. 2022 Mar 21. pii: S1097-2765(22)00214-3. doi:, 10.1016/j.molcel.2022.03.005. PMID:35353987 doi:http://dx.doi.org/10.1016/j.molcel.2022.03.005

7p7h, resolution 2.40Å

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