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==Crystal structure of the PH-like domain from DENND3==
==Crystal structure of the PH-like domain from DENND3==
<StructureSection load='6b3y' size='340' side='right' caption='[[6b3y]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
<StructureSection load='6b3y' size='340' side='right'caption='[[6b3y]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6b3y]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B3Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B3Y FirstGlance]. <br>
<table><tr><td colspan='2'>[[6b3y]] 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=6B3Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B3Y FirstGlance]. <br>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Dennd3, Kiaa0870 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.852&#8491;</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=6b3y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b3y OCA], [http://pdbe.org/6b3y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b3y RCSB], [http://www.ebi.ac.uk/pdbsum/6b3y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b3y ProSAT]</span></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=6b3y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b3y OCA], [https://pdbe.org/6b3y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b3y RCSB], [https://www.ebi.ac.uk/pdbsum/6b3y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b3y ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/DEND3_MOUSE DEND3_MOUSE]] Guanine nucleotide exchange factor (GEF) activating Rab12. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab12 into its active GTP-bound form. Regulates autophagy in response to starvation through Rab12 activation (PubMed:24719330, PubMed:25925668, PubMed:28249939). Starvation leads to ULK1/2-dependent phosphorylation of Ser-554 and Ser-572, which in turn allows recruitment of 14-3-3 adapter proteins and leads to up-regulation of GEF activity towards Rab12 (PubMed:25925668). Also plays a role in protein transport from recycling endosomes to lysosomes, regulating, for instance, the degradation of the transferrin receptor and of the amino acid transporter PAT4 (PubMed:21718402, PubMed:24719330). Starvation also induces phosphorylation at Tyr-940, which leads to up-regulated GEF activity and initiates autophagy (PubMed:28249939).<ref>PMID:21718402</ref> <ref>PMID:24719330</ref> <ref>PMID:25925668</ref> <ref>PMID:28249939</ref> 
[https://www.uniprot.org/uniprot/DEND3_MOUSE DEND3_MOUSE] Guanine nucleotide exchange factor (GEF) activating Rab12. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab12 into its active GTP-bound form. Regulates autophagy in response to starvation through Rab12 activation (PubMed:24719330, PubMed:25925668, PubMed:28249939). Starvation leads to ULK1/2-dependent phosphorylation of Ser-554 and Ser-572, which in turn allows recruitment of 14-3-3 adapter proteins and leads to up-regulation of GEF activity towards Rab12 (PubMed:25925668). Also plays a role in protein transport from recycling endosomes to lysosomes, regulating, for instance, the degradation of the transferrin receptor and of the amino acid transporter PAT4 (PubMed:21718402, PubMed:24719330). Starvation also induces phosphorylation at Tyr-940, which leads to up-regulated GEF activity and initiates autophagy (PubMed:28249939).<ref>PMID:21718402</ref> <ref>PMID:24719330</ref> <ref>PMID:25925668</ref> <ref>PMID:28249939</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Rab GTPases are key regulators of membrane trafficking, and many are activated by guanine nucleotide exchange factors bearing a differentially expressed in normal and neoplastic cells (DENN) domain. By activating the small GTPase Rab12, DENN domain-containing protein 3 (DENND3) functions in autophagy. Here, we identified a structural domain (which we name PHenn) containing a pleckstrin homology subdomain that binds actin and is required for DENND3 function in autophagy. We found that a hydrophobic patch on an extended beta-turn of the PHenn domain mediates an intramolecular interaction with the DENN domain of DENND3. We also show that DENND3 binds actin through a surface of positively charged residues on the PHenn domain. Substitutions that blocked either DENN or actin binding compromised the role of DENND3 in autophagy. These results provide new mechanistic insight into the structural determinants regulating DENND3 in autophagy and lay the foundation for future investigations of the DENN protein family.
 
A PH-like domain of the Rab12 guanine nucleotide exchange factor DENND3 binds actin and is required for autophagy.,Xu J, Kozlov G, McPherson PS, Gehring K J Biol Chem. 2018 Mar 23;293(12):4566-4574. doi: 10.1074/jbc.RA117.001446. Epub, 2018 Jan 19. PMID:29352104<ref>PMID:29352104</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6b3y" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Lk3 transgenic mice]]
[[Category: Large Structures]]
[[Category: Beaugrand, M]]
[[Category: Mus musculus]]
[[Category: Gehring, K]]
[[Category: Beaugrand M]]
[[Category: Kozlov, G]]
[[Category: Gehring K]]
[[Category: McPherson, P S]]
[[Category: Kozlov G]]
[[Category: Menade, M]]
[[Category: McPherson PS]]
[[Category: Pan, T]]
[[Category: Menade M]]
[[Category: Xu, J]]
[[Category: Pan T]]
[[Category: Autophagy]]
[[Category: Xu J]]
[[Category: Guanine nucleotide exchange factor]]
[[Category: Ph-like fold]]
[[Category: Transport protein]]

Latest revision as of 14:19, 13 March 2024

Crystal structure of the PH-like domain from DENND3

6b3y, resolution 1.85Å

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