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==Crystal structure of Casein Kinase I delta (CK1d) in complex with triple phosphorylated p63 PAD3P peptide== | ==Crystal structure of Casein Kinase I delta (CK1d) in complex with triple phosphorylated p63 PAD3P peptide== | ||
<StructureSection load='6ru8' size='340' side='right'caption='[[6ru8]]' scene=''> | <StructureSection load='6ru8' size='340' side='right'caption='[[6ru8]], [[Resolution|resolution]] 1.92Å' 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=6RU8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RU8 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6ru8]] is a 8 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=6RU8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RU8 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ru8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ru8 OCA], [http://pdbe.org/6ru8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ru8 RCSB], [http://www.ebi.ac.uk/pdbsum/6ru8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ru8 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=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CSNK1D, HCKID ([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://proteopedia.org/fgij/fg.htm?mol=6ru8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ru8 OCA], [http://pdbe.org/6ru8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ru8 RCSB], [http://www.ebi.ac.uk/pdbsum/6ru8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ru8 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[http://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. [[http://www.uniprot.org/uniprot/P63_HUMAN P63_HUMAN]] Defects in TP63 are the cause of acro-dermato-ungual-lacrimal-tooth syndrome (ADULT syndrome) [MIM:[http://omim.org/entry/103285 103285]]; a form of ectodermal dysplasia. Ectodermal dysplasias (EDs) constitute a heterogeneous group of developmental disorders affecting tissues of ectodermal origin. EDs are characterized by abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. ADULT syndrome involves ectrodactyly, syndactyly, finger- and toenail dysplasia, hypoplastic breasts and nipples, intensive freckling, lacrimal duct atresia, frontal alopecia, primary hypodontia, and loss of permanent teeth. ADULT differs significantly from EEC3 syndrome by the absence of facial clefting. Defects in TP63 are the cause of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) [MIM:[http://omim.org/entry/106260 106260]]. AEC is an autosomal dominant condition characterized by congenital ectodermal dysplasia with coarse, wiry, sparse hair, dystrophic nails, slight hypohidrosis, scalp infections, ankyloblepharon filiform adnatum, maxillary hypoplasia, hypodontia and cleft lip/palate.<ref>PMID:11159940</ref> Defects in TP63 are the cause of ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome type 3 (EEC3) [MIM:[http://omim.org/entry/604292 604292]]. EEC3 is an autosomal dominant syndrome characterized by ectrodactyly of hands and feet, ectodermal dysplasia and facial clefting.<ref>PMID:10535733</ref> <ref>PMID:10839977</ref> <ref>PMID:11462173</ref> <ref>PMID:12838557</ref> Defects in TP63 are the cause of split-hand/foot malformation type 4 (SHFM4) [MIM:[http://omim.org/entry/605289 605289]]. Split-hand/split-foot malformation is a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. There is restricted overlap between the mutational spectra of EEC3 and SHFM4.<ref>PMID:10839977</ref> <ref>PMID:11462173</ref> Defects in TP63 are the cause of limb-mammary syndrome (LMS) [MIM:[http://omim.org/entry/603543 603543]]. LMS is characterized by ectrodactyly, cleft palate and mammary-gland abnormalities.<ref>PMID:11462173</ref> Note=Defects in TP63 are a cause of cervical, colon, head and neck, lung and ovarian cancers. Defects in TP63 are a cause of ectodermal dysplasia Rapp-Hodgkin type (EDRH) [MIM:[http://omim.org/entry/129400 129400]]; also called Rapp-Hodgkin syndrome or anhidrotic ectodermal dysplasia with cleft lip/palate. Ectodermal dysplasia defines a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. EDRH is characterized by the combination of anhidrotic ectodermal dysplasia, cleft lip, and cleft palate. The clinical syndrome is comprised of a characteristic facies (narrow nose and small mouth), wiry, slow-growing, and uncombable hair, sparse eyelashes and eyebrows, obstructed lacrimal puncta/epiphora, bilateral stenosis of external auditory canals, microsomia, hypodontia, cone-shaped incisors, enamel hypoplasia, dystrophic nails, and cleft lip/cleft palate.<ref>PMID:12939657</ref> <ref>PMID:12766194</ref> <ref>PMID:15200513</ref> <ref>PMID:16740912</ref> Defects in TP63 are the cause of non-syndromic orofacial cleft type 8 (OFC8) [MIM:[http://omim.org/entry/129400 129400]]. Non-syndromic orofacial cleft is a common birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. | |||
== Function == | |||
[[http://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> [[http://www.uniprot.org/uniprot/P63_HUMAN P63_HUMAN]] Acts as a sequence specific DNA binding transcriptional activator or repressor. The isoforms contain a varying set of transactivation and auto-regulating transactivation inhibiting domains thus showing an isoform specific activity. Isoform 2 activates RIPK4 transcription. May be required in conjunction with TP73/p73 for initiation of p53/TP53 dependent apoptosis in response to genotoxic insults and the presence of activated oncogenes. Involved in Notch signaling by probably inducing JAG1 and JAG2. Plays a role in the regulation of epithelial morphogenesis. The ratio of DeltaN-type and TA*-type isoforms may govern the maintenance of epithelial stem cell compartments and regulate the initiation of epithelial stratification from the undifferentiated embryonal ectoderm. Required for limb formation from the apical ectodermal ridge. Activates transcription of the p21 promoter.<ref>PMID:9774969</ref> <ref>PMID:11641404</ref> <ref>PMID:12446779</ref> <ref>PMID:12446784</ref> <ref>PMID:12374749</ref> <ref>PMID:20123734</ref> <ref>PMID:22197488</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The p53 homolog TAp63alpha is the transcriptional key regulator of genome integrity in oocytes. After DNA damage, TAp63alpha is activated by multistep phosphorylation involving multiple phosphorylation events by the kinase CK1, which triggers the transition from a dimeric and inactive conformation to an open and active tetramer that initiates apoptosis. By measuring activation kinetics in ovaries and single-site phosphorylation kinetics in vitro with peptides and full-length protein, we show that TAp63alpha phosphorylation follows a biphasic behavior. Although the first two CK1 phosphorylation events are fast, the third one, which constitutes the decisive step to form the active conformation, is slow. Structure determination of CK1 in complex with differently phosphorylated peptides reveals the structural mechanism for the difference in the kinetic behavior based on an unusual CK1/TAp63alpha substrate interaction in which the product of one phosphorylation step acts as an inhibitor for the following one. | |||
p63 uses a switch-like mechanism to set the threshold for induction of apoptosis.,Gebel J, Tuppi M, Chaikuad A, Hotte K, Schroder M, Schulz L, Lohr F, Gutfreund N, Finke F, Henrich E, Mezhyrova J, Lehnert R, Pampaloni F, Hummer G, Stelzer EHK, Knapp S, Dotsch V Nat Chem Biol. 2020 Jul 27. pii: 10.1038/s41589-020-0600-3. doi:, 10.1038/s41589-020-0600-3. PMID:32719556<ref>PMID:32719556</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ru8" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Casein kinase 3D structures|Casein kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Arrowsmith | [[Category: Arrowsmith, C H]] | ||
[[Category: Bountra C]] | [[Category: Bountra, C]] | ||
[[Category: Chaikuad A]] | [[Category: Chaikuad, A]] | ||
[[Category: Dotsch V]] | [[Category: Dotsch, V]] | ||
[[Category: Edwards | [[Category: Edwards, A M]] | ||
[[Category: Gebel J]] | [[Category: Gebel, J]] | ||
[[Category: Knapp S]] | [[Category: Knapp, S]] | ||
[[Category: Tuppi M]] | [[Category: Structural genomic]] | ||
[[Category: Tuppi, M]] | |||
[[Category: Ck1 delta]] | |||
[[Category: Ck1delta]] | |||
[[Category: Csnk1d]] | |||
[[Category: Kinase substrate complex]] | |||
[[Category: P63]] | |||
[[Category: Sgc]] | |||
[[Category: Tp63]] | |||
[[Category: Transferase]] | |||