3mft: Difference between revisions
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== | ==CASK-4M CaM Kinase Domain, Mn2+== | ||
[[http://www.uniprot.org/uniprot/CSKP_HUMAN CSKP_HUMAN | <StructureSection load='3mft' size='340' side='right'caption='[[3mft]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3mft]] is a 1 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=3MFT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MFT FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</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=3mft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mft OCA], [https://pdbe.org/3mft PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mft RCSB], [https://www.ebi.ac.uk/pdbsum/3mft PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mft ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/CSKP_HUMAN CSKP_HUMAN] Defects in CASK are the cause of mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [MIM:[https://omim.org/entry/300749 300749]. A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Patients with mental retardation X-linked CASK-related can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of mental retardation alone or associated with nystagmus.<ref>PMID:19165920</ref> Defects in CASK are the cause of FG syndrome type 4 (FGS4) [MIM:[https://omim.org/entry/300422 300422]. FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation.<ref>PMID:19200522</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CSKP_HUMAN CSKP_HUMAN] Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TRB1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1. | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mf/3mft_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3mft ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
All known protein kinases, except CASK [calcium/calmodulin (CaM)-activated serine-threonine kinase], require magnesium ions (Mg(2+)) to stimulate the transfer of a phosphate from adenosine 5'-triphosphate (ATP) to a protein substrate. The CaMK (calcium/calmodulin-dependent kinase) domain of CASK shows activity in the absence of Mg(2+); indeed, it is inhibited by divalent ions including Mg(2+). Here, we converted the Mg(2+)-inhibited wild-type CASK kinase (CASK(WT)) into a Mg(2+)-stimulated kinase (CASK(4M)) by substituting four residues within the ATP-binding pocket. Crystal structures of CASK(4M) with and without bound nucleotide and Mn(2+), together with kinetic analyses, demonstrated that Mg(2+) accelerates catalysis of CASK(4M) by stabilizing the transition state, enhancing the leaving group properties of adenosine 5'-diphosphate, and indirectly shifting the position of the gamma-phosphate of ATP. Phylogenetic analysis revealed that the four residues conferring Mg(2+)-mediated stimulation were substituted from CASK during early animal evolution, converting a primordial, Mg(2+)-coordinating form of CASK into a Mg(2+)-inhibited kinase. This emergence of Mg(2+) sensitivity (inhibition by Mg(2+)) conferred regulation of CASK activity by divalent cations, in parallel with the evolution of the animal nervous systems. | |||
Evolution of CASK into a Mg2+-sensitive kinase.,Mukherjee K, Sharma M, Jahn R, Wahl MC, Sudhof TC Sci Signal. 2010 Apr 27;3(119):ra33. PMID:20424264<ref>PMID:20424264</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3mft" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Calcium/calmodulin dependent protein kinase 3D structures|Calcium/calmodulin dependent protein kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Mukherjee | [[Category: Mukherjee K]] | ||
[[Category: Wahl | [[Category: Wahl MC]] | ||
