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2iep

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(New page: 200px<br /><applet load="2iep" size="450" color="white" frame="true" align="right" spinBox="true" caption="2iep, resolution 2.205&Aring;" /> '''Crystal structure o...)
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[[Image:2iep.gif|left|200px]]<br /><applet load="2iep" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2iep, resolution 2.205&Aring;" />
 
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'''Crystal structure of immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK'''<br />
 
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==Overview==
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==Crystal structure of immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK==
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Muscle-specific kinase (MuSK) is a receptor tyrosine kinase expressed, exclusively in skeletal muscle, where it is required for formation of the, neuromuscular junction. MuSK is activated by agrin, a neuron-derived, heparan sulfate proteoglycan. Here, we report the crystal structure of the, agrin-responsive first and second immunoglobulin-like domains (Ig1 and, Ig2) of the MuSK ectodomain at 2.2 A resolution. The structure reveals, that MuSK Ig1 and Ig2 are Ig-like domains of the I-set subfamily, which, are configured in a linear, semi-rigid arrangement. In addition to the, canonical internal disulfide bridge, Ig1 contains a second, solvent-exposed disulfide bridge, which our biochemical data indicate is, critical for proper folding of Ig1 and processing of MuSK. Two Ig1-2, molecules form a non-crystallographic dimer that is mediated by a unique, hydrophobic patch on the surface of Ig1. Biochemical analyses of MuSK, mutants introduced into MuSK(-/-) myotubes demonstrate that residues in, this hydrophobic patch are critical for agrin-induced MuSK activation.
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<StructureSection load='2iep' size='340' side='right'caption='[[2iep]], [[Resolution|resolution]] 2.21&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2iep]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IEP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IEP FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.205&#8491;</td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2iep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2iep OCA], [https://pdbe.org/2iep PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2iep RCSB], [https://www.ebi.ac.uk/pdbsum/2iep PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2iep ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/MUSK_RAT MUSK_RAT] Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle. Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation.<ref>PMID:16870737</ref> <ref>PMID:17011580</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ie/2iep_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2iep ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Muscle-specific kinase (MuSK) is a receptor tyrosine kinase expressed exclusively in skeletal muscle, where it is required for formation of the neuromuscular junction. MuSK is activated by agrin, a neuron-derived heparan sulfate proteoglycan. Here, we report the crystal structure of the agrin-responsive first and second immunoglobulin-like domains (Ig1 and Ig2) of the MuSK ectodomain at 2.2 A resolution. The structure reveals that MuSK Ig1 and Ig2 are Ig-like domains of the I-set subfamily, which are configured in a linear, semi-rigid arrangement. In addition to the canonical internal disulfide bridge, Ig1 contains a second, solvent-exposed disulfide bridge, which our biochemical data indicate is critical for proper folding of Ig1 and processing of MuSK. Two Ig1-2 molecules form a non-crystallographic dimer that is mediated by a unique hydrophobic patch on the surface of Ig1. Biochemical analyses of MuSK mutants introduced into MuSK(-/-) myotubes demonstrate that residues in this hydrophobic patch are critical for agrin-induced MuSK activation.
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==About this Structure==
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Crystal structure of the agrin-responsive immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK.,Stiegler AL, Burden SJ, Hubbard SR J Mol Biol. 2006 Dec 1;364(3):424-33. Epub 2006 Sep 12. PMID:17011580<ref>PMID:17011580</ref>
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2IEP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with SO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2IEP OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Crystal structure of the agrin-responsive immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK., Stiegler AL, Burden SJ, Hubbard SR, J Mol Biol. 2006 Dec 1;364(3):424-33. Epub 2006 Sep 12. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17011580 17011580]
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</div>
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[[Category: Rattus norvegicus]]
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<div class="pdbe-citations 2iep" style="background-color:#fffaf0;"></div>
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[[Category: Receptor protein-tyrosine kinase]]
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[[Category: Single protein]]
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[[Category: Burden, S.J.]]
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[[Category: Hubbard, S.R.]]
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[[Category: Stiegler, A.L.]]
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[[Category: SO4]]
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[[Category: beta-sandwich]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 12:17:03 2007''
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==See Also==
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*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Rattus norvegicus]]
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[[Category: Burden SJ]]
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[[Category: Hubbard SR]]
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[[Category: Stiegler AL]]

Current revision

Crystal structure of immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK

PDB ID 2iep

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