Structural highlights
Function
[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).[1] [2] [3] [4]
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[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Matsui T, Itoh T, Fukuda M. Small GTPase Rab12 regulates constitutive degradation of transferrin receptor. Traffic. 2011 Oct;12(10):1432-43. doi: 10.1111/j.1600-0854.2011.01240.x. Epub, 2011 Jul 29. PMID:21718402 doi:http://dx.doi.org/10.1111/j.1600-0854.2011.01240.x
- ↑ Matsui T, Noguchi K, Fukuda M. Dennd3 functions as a guanine nucleotide exchange factor for small GTPase Rab12 in mouse embryonic fibroblasts. J Biol Chem. 2014 May 16;289(20):13986-95. doi: 10.1074/jbc.M113.546689. Epub, 2014 Apr 9. PMID:24719330 doi:http://dx.doi.org/10.1074/jbc.M113.546689
- ↑ Xu J, Fotouhi M, McPherson PS. Phosphorylation of the exchange factor DENND3 by ULK in response to starvation activates Rab12 and induces autophagy. EMBO Rep. 2015 Jun;16(6):709-18. doi: 10.15252/embr.201440006. Epub 2015 Apr 29. PMID:25925668 doi:http://dx.doi.org/10.15252/embr.201440006
- ↑ Xu J, McPherson PS. Regulation of DENND3, the exchange factor for the small GTPase Rab12 through an intramolecular interaction. J Biol Chem. 2017 Apr 28;292(17):7274-7282. doi: 10.1074/jbc.M116.772434. Epub, 2017 Mar 1. PMID:28249939 doi:http://dx.doi.org/10.1074/jbc.M116.772434
- ↑ Xu J, Kozlov G, McPherson PS, Gehring K. A PH-like domain of the Rab12 guanine nucleotide exchange factor DENND3 binds actin and is required for autophagy. J Biol Chem. 2018 Mar 23;293(12):4566-4574. doi: 10.1074/jbc.RA117.001446. Epub, 2018 Jan 19. PMID:29352104 doi:http://dx.doi.org/10.1074/jbc.RA117.001446
