View source for 4nol


==Crystal structure of proenzyme asparaginyl endopeptidase (AEP)/Legumain mutant D233A at pH 7.5==
<StructureSection load='4nol' size='340' side='right'caption='[[4nol]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4nol]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NOL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NOL 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]] 2.7&#8491;</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=4nol FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nol OCA], [https://pdbe.org/4nol PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nol RCSB], [https://www.ebi.ac.uk/pdbsum/4nol PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nol ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/LGMN_MOUSE LGMN_MOUSE] Has a strict specificity for hydrolysis of asparaginyl bonds. Can also cleave aspartyl bonds slowly, especially under acidic conditions. May be involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system. Required for normal lysosomal protein degradation in renal proximal tubules. Required for normal degradation of internalized EGFR. Plays a role in the regulation of cell proliferation via its role in EGFR degradation.<ref>PMID:9742219</ref> <ref>PMID:17350006</ref> <ref>PMID:21292981</ref> 
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== Publication Abstract from PubMed ==
Asparaginyl endopeptidase (AEP) is an endo/lysosomal cysteine endopeptidase with a preference for an asparagine residue at the P1 site and plays an important role in the maturation of toll-like receptors 3/7/9. AEP is known to undergo autoproteolytic maturation at acidic pH for catalytic activation. Here, we describe crystal structures of the AEP proenzyme and the mature forms of AEP. Structural comparisons between AEP and caspases revealed similarities in the composition of key residues and in the catalytic mechanism. Mutagenesis studies identified N44, R46, H150, E189, C191, S217/S218 and D233 as residues that are essential for the cleavage of the peptide substrate. During maturation, autoproteolytic cleavage of AEP's cap domain opens up access to the active site on the core domain. Unexpectedly, an intermediate autoproteolytic maturation stage was discovered at approximately pH 4.5 in which the partially activated AEP could be reversed back to its proenzyme form. This unique feature was confirmed by the crystal structure of AEPpH4.5 (AEP was matured at pH 4.5 and crystallized at pH 8.5), in which the broken peptide bonds were religated and the structure was transformed back to its proenzyme form. Additionally, the AEP inhibitor cystatin C could be digested by the fully activated AEP, but could not be digested by activated cathepsins. Thus, we demonstrate for the first time that cystatins may regulate the activity of AEP through substrate competition for the active site.Cell Research advance online publication 10 January 2014; doi:10.1038/cr.2014.4.

Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage.,Zhao L, Hua T, Crowley C, Ru H, Ni X, Shaw N, Jiao L, Ding W, Qu L, Hung LW, Huang W, Liu L, Ye K, Ouyang S, Cheng G, Liu ZJ Cell Res. 2014 Jan 10. doi: 10.1038/cr.2014.4. PMID:24407422<ref>PMID:24407422</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4nol" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Ding W]]
[[Category: Hua T]]
[[Category: Jiao L]]
[[Category: Liu ZJ]]
[[Category: Ni X]]
[[Category: Ouyang S]]
[[Category: Qu L]]
[[Category: Ru H]]
[[Category: Shaw N]]
[[Category: Zhao L]]