3v65: Difference between revisions
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[[ | ==Crystal structure of agrin and LRP4 complex== | ||
<StructureSection load='3v65' size='340' side='right' caption='[[3v65]], [[Resolution|resolution]] 3.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3v65]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V65 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3V65 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3v64|3v64]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Agrn, Agrin ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus]), Lrp4, Megf7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3v65 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v65 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3v65 RCSB], [http://www.ebi.ac.uk/pdbsum/3v65 PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/AGRIN_RAT AGRIN_RAT]] Isoform 1: heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ) and directs key events in postsynaptic differentiation. This neuron-specific (z+) isoform is a component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Calcium ions are required for maximal AChR clustering. AGRN function in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homestasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This transmembrane agrin (TM-agrin) isoform, the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases.<ref>PMID:8398142</ref> <ref>PMID:8653787</ref> <ref>PMID:8693000</ref> <ref>PMID:18775496</ref> <ref>PMID:19524020</ref> <ref>PMID:20471381</ref> <ref>PMID:20566625</ref> <ref>PMID:20505824</ref> Isoform 1, isoform 4, isoform 5 and isoform 6: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms.<ref>PMID:8398142</ref> <ref>PMID:8653787</ref> <ref>PMID:8693000</ref> <ref>PMID:18775496</ref> <ref>PMID:19524020</ref> <ref>PMID:20471381</ref> <ref>PMID:20566625</ref> <ref>PMID:20505824</ref> Agrin N-terminal 110 kDa subunit: is involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling (By similarity).<ref>PMID:8398142</ref> <ref>PMID:8653787</ref> <ref>PMID:8693000</ref> <ref>PMID:18775496</ref> <ref>PMID:19524020</ref> <ref>PMID:20471381</ref> <ref>PMID:20566625</ref> <ref>PMID:20505824</ref> Agrin C-terminal 22 kDa fragment: this released fragment is important for agrin signaling and to exert a maximal dendritic filopodia-inducing effect. All 'z' splice variants (z+) of this fragment also show an increase in the number of filopodia.<ref>PMID:8398142</ref> <ref>PMID:8653787</ref> <ref>PMID:8693000</ref> <ref>PMID:18775496</ref> <ref>PMID:19524020</ref> <ref>PMID:20471381</ref> <ref>PMID:20566625</ref> <ref>PMID:20505824</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Synapses are the fundamental units of neural circuits that enable complex behaviors. The neuromuscular junction (NMJ), a synapse formed between a motoneuron and a muscle fiber, has contributed greatly to understanding of the general principles of synaptogenesis as well as of neuromuscular disorders. NMJ formation requires neural agrin, a motoneuron-derived protein, which interacts with LRP4 (low-density lipoprotein receptor-related protein 4) to activate the receptor tyrosine kinase MuSK (muscle-specific kinase). However, little is known of how signals are transduced from agrin to MuSK. Here, we present the first crystal structure of an agrin-LRP4 complex, consisting of two agrin-LRP4 heterodimers. Formation of the initial binary complex requires the z8 loop that is specifically present in neuronal, but not muscle, agrin and that promotes the synergistic formation of the tetramer through two additional interfaces. We show that the tetrameric complex is essential for neuronal agrin-induced acetylcholine receptor (AChR) clustering. Collectively, these results provide new insight into the agrin-LRP4-MuSK signaling cascade and NMJ formation and represent a novel mechanism for activation of receptor tyrosine kinases. | |||
Structural basis of agrin-LRP4-MuSK signaling.,Zong Y, Zhang B, Gu S, Lee K, Zhou J, Yao G, Figueiredo D, Perry K, Mei L, Jin R Genes Dev. 2012 Feb 1;26(3):247-58. doi: 10.1101/gad.180885.111. PMID:22302937<ref>PMID:22302937</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Agrin|Agrin]] | *[[Agrin|Agrin]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Jin, R | [[Category: Jin, R]] | ||
[[Category: Zong, Y | [[Category: Zong, Y]] | ||
[[Category: Beta-propeller]] | [[Category: Beta-propeller]] | ||
[[Category: Laminin-g]] | [[Category: Laminin-g]] | ||
[[Category: Protein binding]] | [[Category: Protein binding]] | ||