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[[Image:2jmf.jpg|left|200px]]<br /><applet load="2jmf" size="350" color="white" frame="true" align="right" spinBox="true"
caption="2jmf" />
'''Solution structure of the Su(dx) WW4- Notch PY peptide complex'''<br />


==Overview==
==Solution structure of the Su(dx) WW4- Notch PY peptide complex==
WW domains target proline-tyrosine (PY) motifs and frequently function as, tandem pairs. When studied in isolation, single WW domains are notably, promiscuous and regulatory mechanisms are undoubtedly required to ensure, selective interactions. Here, we show that the fourth WW domain (WW4) of, Suppressor of deltex, a modular Nedd4-like protein that down-regulates the, Notch receptor, is the primary mediator of a direct interaction with a, Notch-PY motif. A natural Trp to Phe substitution in WW4 reduces its, affinity for general PY sequences and enhances selective interaction with, the Notch-PY motif via compensatory specificity-determining interactions, with PY-flanking residues. When WW4 is paired with WW3, domain-domain, association, impeding proper folding, competes with Notch-PY binding to, WW4. This novel mode of autoinhibition is relieved by binding of another, ligand to WW3. Such cooperativity may facilitate the transient regulatory, interactions observed in vivo between Su(dx) and Notch in the endocytic, pathway. The highly conserved tandem arrangement of WW domains in Nedd4, proteins, and similar arrangements in more diverse proteins, suggests, domain-domain communication may be integral to regulation of their, associated cellular activities.
<StructureSection load='2jmf' size='340' side='right'caption='[[2jmf]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2jmf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JMF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2JMF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=2jmf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2jmf OCA], [https://pdbe.org/2jmf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2jmf RCSB], [https://www.ebi.ac.uk/pdbsum/2jmf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2jmf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SUDX_DROME SUDX_DROME] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Down-regulates Notch/N signaling pathway, probably by promoting Notch ubiquitination, endocytosis and degradation. Involved in wing growth and leg joint formation.<ref>PMID:12648496</ref> <ref>PMID:15620650</ref>
== 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/jm/2jmf_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=2jmf ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
WW domains target proline-tyrosine (PY) motifs and frequently function as tandem pairs. When studied in isolation, single WW domains are notably promiscuous and regulatory mechanisms are undoubtedly required to ensure selective interactions. Here, we show that the fourth WW domain (WW4) of Suppressor of Deltex, a modular Nedd4-like protein that down-regulates the Notch receptor, is the primary mediator of a direct interaction with a Notch-PY motif. A natural Trp to Phe substitution in WW4 reduces its affinity for general PY sequences and enhances selective interaction with the Notch-PY motif via compensatory specificity-determining interactions with PY-flanking residues. When WW4 is paired with WW3, domain-domain association, impeding proper folding, competes with Notch-PY binding to WW4. This novel mode of autoinhibition is relieved by binding of another ligand to WW3. Such cooperativity may facilitate the transient regulatory interactions observed in vivo between Su(dx) and Notch in the endocytic pathway. The highly conserved tandem arrangement of WW domains in Nedd4 proteins, and similar arrangements in more diverse proteins, suggests domain-domain communication may be integral to regulation of their associated cellular activities.


==About this Structure==
Specificity and autoregulation of Notch binding by tandem WW domains in suppressor of Deltex.,Jennings MD, Blankley RT, Baron M, Golovanov AP, Avis JM J Biol Chem. 2007 Sep 28;282(39):29032-42. Epub 2007 Jul 26. PMID:17656366<ref>PMID:17656366</ref>
2JMF is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JMF OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
Specificity and autoregulation of notch binding by tandem WW domains in suppressor of deltex., Jennings MD, Blankley RT, Baron M, Golovanov AP, Avis JM, J Biol Chem. 2007 Jul 26;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17656366 17656366]
</div>
<div class="pdbe-citations 2jmf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Drosophila melanogaster]]
[[Category: Drosophila melanogaster]]
[[Category: Protein complex]]
[[Category: Large Structures]]
[[Category: Avis, J.M.]]
[[Category: Avis JM]]
[[Category: Blankley, R.T.]]
[[Category: Blankley RT]]
[[Category: Golovanov, A.P.]]
[[Category: Golovanov AP]]
[[Category: Jennings, M.D.]]
[[Category: Jennings MD]]
[[Category: complex]]
[[Category: ligase/signaling protein complex]]
[[Category: nmr solution]]
[[Category: notch]]
[[Category: ww domain]]
 
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