DEND3_MOUSE
ID DEND3_MOUSE Reviewed; 1274 AA.
AC A2RT67; B2RQ75; Q69ZX2; Q8C6V5;
DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
DT 20-MAR-2007, sequence version 2.
DT 03-AUG-2022, entry version 121.
DE RecName: Full=DENN domain-containing protein 3;
GN Name=Dennd3; Synonyms=Kiaa0870;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15368895; DOI=10.1093/dnares/11.3.205;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Seino S., Nishimura M., Kaisho T., Hoshino K., Kitamura H.,
RA Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: IV.
RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 11:205-218(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 495-1274.
RC STRAIN=C57BL/6J; TISSUE=Lung;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP FUNCTION.
RX PubMed=21718402; DOI=10.1111/j.1600-0854.2011.01240.x;
RA Matsui T., Itoh T., Fukuda M.;
RT "Small GTPase Rab12 regulates constitutive degradation of transferrin
RT receptor.";
RL Traffic 12:1432-1443(2011).
RN [6]
RP FUNCTION.
RX PubMed=24719330; DOI=10.1074/jbc.m113.546689;
RA Matsui T., Noguchi K., Fukuda M.;
RT "Dennd3 functions as a guanine nucleotide exchange factor for small GTPase
RT Rab12 in mouse embryonic fibroblasts.";
RL J. Biol. Chem. 289:13986-13995(2014).
RN [7]
RP FUNCTION, SUBUNIT, PHOSPHORYLATION AT SER-554 AND SER-572, AND MUTAGENESIS
RP OF SER-554 AND SER-572.
RX PubMed=25925668; DOI=10.15252/embr.201440006;
RA Xu J., Fotouhi M., McPherson P.S.;
RT "Phosphorylation of the exchange factor DENND3 by ULK in response to
RT starvation activates Rab12 and induces autophagy.";
RL EMBO Rep. 16:709-718(2015).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, PHOSPHORYLATION AT TYR-940, AND
RP MUTAGENESIS OF TYR-940.
RX PubMed=28249939; DOI=10.1074/jbc.m116.772434;
RA Xu J., McPherson P.S.;
RT "Regulation of DENND3, the exchange factor for the small GTPase Rab12
RT through an intramolecular interaction.";
RL J. Biol. Chem. 292:7274-7282(2017).
CC -!- FUNCTION: Guanine nucleotide exchange factor (GEF) activating Rab12.
CC Promotes the exchange of GDP to GTP, converting inactive GDP-bound
CC Rab12 into its active GTP-bound form. Regulates autophagy in response
CC to starvation through Rab12 activation (PubMed:24719330,
CC PubMed:25925668, PubMed:28249939). Starvation leads to ULK1/2-dependent
CC phosphorylation of Ser-554 and Ser-572, which in turn allows
CC recruitment of 14-3-3 adapter proteins and leads to up-regulation of
CC GEF activity towards Rab12 (PubMed:25925668). Also plays a role in
CC protein transport from recycling endosomes to lysosomes, regulating,
CC for instance, the degradation of the transferrin receptor and of the
CC amino acid transporter PAT4 (PubMed:21718402, PubMed:24719330).
CC Starvation also induces phosphorylation at Tyr-940, which leads to up-
CC regulated GEF activity and initiates autophagy (PubMed:28249939).
CC {ECO:0000269|PubMed:21718402, ECO:0000269|PubMed:24719330,
CC ECO:0000269|PubMed:25925668, ECO:0000269|PubMed:28249939}.
CC -!- SUBUNIT: Forms oligomers (PubMed:28249939). Interacts with 6 of the 7
CC known isoforms of 14-3-3 proteins (PubMed:25925668).
CC {ECO:0000269|PubMed:25925668, ECO:0000269|PubMed:28249939}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:28249939}.
CC Note=Transiently recruited to membranes to activate Rab12.
CC {ECO:0000269|PubMed:28249939}.
CC -!- DOMAIN: Inactive Dennd3 is found in a closed conformation, in which the
CC linker region interacts with the DENN domain. Phosphorylation of Tyr-
CC 940 in the linker region intereferes with this interaction leading to
CC an open conformation and enhances the GEF activity of the protein
CC towards Rab12. {ECO:0000269|PubMed:28249939}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC35269.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAD32324.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AK173046; BAD32324.1; ALT_INIT; mRNA.
DR EMBL; BC132389; AAI32390.2; -; mRNA.
DR EMBL; BC137791; AAI37792.1; -; mRNA.
DR EMBL; AK053114; BAC35269.1; ALT_INIT; mRNA.
DR CCDS; CCDS37100.1; -.
DR RefSeq; NP_001074535.1; NM_001081066.1.
DR PDB; 6B3Y; X-ray; 1.85 A; A/B=720-973.
DR PDBsum; 6B3Y; -.
DR AlphaFoldDB; A2RT67; -.
DR SMR; A2RT67; -.
DR BioGRID; 222932; 4.
DR STRING; 10090.ENSMUSP00000046774; -.
DR iPTMnet; A2RT67; -.
DR PhosphoSitePlus; A2RT67; -.
DR EPD; A2RT67; -.
DR MaxQB; A2RT67; -.
DR PaxDb; A2RT67; -.
DR PeptideAtlas; A2RT67; -.
DR PRIDE; A2RT67; -.
DR ProteomicsDB; 279624; -.
DR Antibodypedia; 27680; 38 antibodies from 16 providers.
DR Ensembl; ENSMUST00000043414; ENSMUSP00000046774; ENSMUSG00000036661.
DR GeneID; 105841; -.
DR KEGG; mmu:105841; -.
DR UCSC; uc007wce.1; mouse.
DR CTD; 22898; -.
DR MGI; MGI:2146009; Dennd3.
DR VEuPathDB; HostDB:ENSMUSG00000036661; -.
DR eggNOG; KOG2127; Eukaryota.
DR GeneTree; ENSGT00940000155784; -.
DR InParanoid; A2RT67; -.
DR OMA; MVAMVCN; -.
DR OrthoDB; 521943at2759; -.
DR PhylomeDB; A2RT67; -.
DR TreeFam; TF331814; -.
DR Reactome; R-MMU-8876198; RAB GEFs exchange GTP for GDP on RABs.
DR BioGRID-ORCS; 105841; 2 hits in 71 CRISPR screens.
DR ChiTaRS; Dennd3; mouse.
DR PRO; PR:A2RT67; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; A2RT67; protein.
DR Bgee; ENSMUSG00000036661; Expressed in granulocyte and 154 other tissues.
DR ExpressionAtlas; A2RT67; baseline and differential.
DR Genevisible; A2RT67; MM.
DR GO; GO:0031410; C:cytoplasmic vesicle; IBA:GO_Central.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IGI:UniProtKB.
DR GO; GO:0008333; P:endosome to lysosome transport; IGI:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; IMP:UniProtKB.
DR GO; GO:0032483; P:regulation of Rab protein signal transduction; IBA:GO_Central.
DR Gene3D; 2.130.10.10; -; 1.
DR Gene3D; 3.40.50.11500; -; 1.
DR InterPro; IPR001194; cDENN_dom.
DR InterPro; IPR005112; dDENN_dom.
DR InterPro; IPR043153; DENN_C.
DR InterPro; IPR037516; Tripartite_DENN.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR019775; WD40_repeat_CS.
DR InterPro; IPR036322; WD40_repeat_dom_sf.
DR Pfam; PF02141; DENN; 1.
DR SMART; SM00801; dDENN; 1.
DR SMART; SM00799; DENN; 1.
DR SMART; SM00320; WD40; 3.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS50211; DENN; 1.
DR PROSITE; PS00678; WD_REPEATS_1; 1.
DR PROSITE; PS50082; WD_REPEATS_2; 1.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Guanine-nucleotide releasing factor;
KW Phosphoprotein; Reference proteome; Repeat; WD repeat.
FT CHAIN 1..1274
FT /note="DENN domain-containing protein 3"
FT /id="PRO_0000304673"
FT DOMAIN 75..245
FT /note="uDENN"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00304"
FT DOMAIN 268..400
FT /note="cDENN"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00304"
FT DOMAIN 402..506
FT /note="dDENN"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00304"
FT REPEAT 975..1013
FT /note="WD 1"
FT /evidence="ECO:0000255"
FT REPEAT 1019..1055
FT /note="WD 2"
FT /evidence="ECO:0000255"
FT REPEAT 1059..1099
FT /note="WD 3"
FT /evidence="ECO:0000255"
FT REPEAT 1103..1140
FT /note="WD 4"
FT /evidence="ECO:0000255"
FT REPEAT 1146..1181
FT /note="WD 5"
FT /evidence="ECO:0000255"
FT REPEAT 1186..1228
FT /note="WD 6"
FT /evidence="ECO:0000255"
FT REPEAT 1234..1273
FT /note="WD 7"
FT /evidence="ECO:0000255"
FT REGION 65..108
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 520..970
FT /note="Linker"
FT /evidence="ECO:0000305"
FT COMPBIAS 87..104
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 554
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000269|PubMed:25925668"
FT MOD_RES 572
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000269|PubMed:25925668"
FT MOD_RES 940
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:28249939"
FT MUTAGEN 554
FT /note="S->A: Abolishes interaction with 14-3-3 proteins."
FT /evidence="ECO:0000269|PubMed:25925668"
FT MUTAGEN 572
FT /note="S->A: Greatly reduces interaction with 14-3-3
FT proteins."
FT /evidence="ECO:0000269|PubMed:25925668"
FT MUTAGEN 940
FT /note="Y->D: Abrogates the intramolecular linker-DENN
FT domain interaction and enhances GEF activity towards
FT Rab12."
FT /evidence="ECO:0000269|PubMed:28249939"
FT MUTAGEN 940
FT /note="Y->F: Retains the intramolecular linker-DENN domain
FT interaction and impairs GEF activity towards Rab12."
FT /evidence="ECO:0000269|PubMed:28249939"
FT CONFLICT 126
FT /note="P -> S (in Ref. 1; BAD32324)"
FT /evidence="ECO:0000305"
FT CONFLICT 1003
FT /note="L -> Q (in Ref. 3; BAC35269)"
FT /evidence="ECO:0000305"
FT CONFLICT 1200
FT /note="T -> N (in Ref. 3; BAC35269)"
FT /evidence="ECO:0000305"
FT HELIX 732..742
FT /evidence="ECO:0007829|PDB:6B3Y"
FT HELIX 748..758
FT /evidence="ECO:0007829|PDB:6B3Y"
FT TURN 759..761
FT /evidence="ECO:0007829|PDB:6B3Y"
FT HELIX 768..786
FT /evidence="ECO:0007829|PDB:6B3Y"
FT HELIX 792..796
FT /evidence="ECO:0007829|PDB:6B3Y"
FT STRAND 804..813
FT /evidence="ECO:0007829|PDB:6B3Y"
FT STRAND 816..835
FT /evidence="ECO:0007829|PDB:6B3Y"
FT STRAND 837..842
FT /evidence="ECO:0007829|PDB:6B3Y"
FT HELIX 843..845
FT /evidence="ECO:0007829|PDB:6B3Y"
FT STRAND 846..856
FT /evidence="ECO:0007829|PDB:6B3Y"
FT STRAND 859..868
FT /evidence="ECO:0007829|PDB:6B3Y"
FT STRAND 875..877
FT /evidence="ECO:0007829|PDB:6B3Y"
FT HELIX 880..882
FT /evidence="ECO:0007829|PDB:6B3Y"
FT HELIX 883..903
FT /evidence="ECO:0007829|PDB:6B3Y"
FT HELIX 907..926
FT /evidence="ECO:0007829|PDB:6B3Y"
FT HELIX 931..935
FT /evidence="ECO:0007829|PDB:6B3Y"
FT HELIX 936..938
FT /evidence="ECO:0007829|PDB:6B3Y"
FT HELIX 940..945
FT /evidence="ECO:0007829|PDB:6B3Y"
SQ SEQUENCE 1274 AA; 143888 MW; 4C465CE967D72DB5 CRC64;
MAEPAARHLS LPSGLLELCA LLGASQDSLR GLEQIAQKRG VKSASSLVPE VLSVFVPPFT
TKEDGQVPGA SCALGKGRRR SFRKKREKPR MEPWKSHPGD SKGPDSEDVT IPGGVDLLAL
PQLCFPGCVC VASEPKEDYI HFLVLTDVCG NRTYGVVAQY YRPLHDEYCF YNGKSHWEPS
VISARCFVPF AVCVVSRFPY YNSLKDCLSC LLTHLKLCKD FEVDNHIKDF AARLSLIPSP
PPGPLHLIFN MKPLQVVFPS RADPESPIVD LDLHLPLLCF RPEKVLQILT CILTEQRIVF
FSSDWALLTL MAECFVAYLH PLQWQHTFVP ILSGQMLDFV MAPTSFLMGC HLDHFEEVRK
EADGLVLIDI DHGSVTCSKS SDDNIDIPDV PLLLAQTFIQ RVQSLQLHPD LHLAHLSAST
DLNEGRARRR AWQQTLNCKI QHITLQLLVG IFREVKNHLN YEHRVFNSEE FLKTRAAGDQ
QFYKQVLDTY MFHSFLKARL NGRMDAFARM DLDTQSEEDR IDRMLISPRR PTVEKMASRK
ASPLHITHRR MVVSMPNLQD ISLPELPPRN SSLRIMDTSN CRSSSPVLKV TPKSTYMFKI
PDIHFPLESQ CVQAYYTDFV TLLSKAMALL GPGDSLLLAR YFYLRGLLHL MQGQLLSALL
DFQNLYKTDI GIFPADLVKR TVESMSASER AQAERTPELR RLITEVFDKH GEAPKADDAV
KNFELPKKHM QLNDFVKRVQ ESGIVKDAVI IHRLFDALTF GHEKQIDPET FRDFYTCWKE
TEAEAQEVSL PALLMEHLDK NECVYKLSSS VKTNRGVGKI AMTQKRLFLL TEGRPGYVEI
ATFRNIEEVK NSTVAFLLLR IPTLKIKTVA KKEVFEANLK SECDLWHLMV KEMWAGKQLA
DDHKDPQYVQ QALTNVLLMD AVVGTLQSPS AIHAASKLAY FDNMKKKSPM AVPKTTSETL
KHKINPSAGE TAPQAIEVLL YTPGRLDPAE KVEDAHPKLW CALNEGKVVV FDASSWTVHQ
HCFKVGSSKV NCMVMAEHNQ VWVGSEDSVI YIINVHSMSC NKQLTDHRSP VTGLAVHNGK
KPSEIYSCSL DGTVIAWNVS TLRVISRFQL SYGDLLSISL HNDRIWCCTV HKILVVTPQG
FVRQELKHPK DASFLAFQLL PEEQQLWAAS TGVSELYMWS LKDLDQPPQK TYLQDCSEVT
CMIRVKRQIW VGGRGLSQGK TRGKIYVMDV EKVTVEKELV AHLDTVRTLC SAEDRYVLSG
AGQEEGKIAI WKVE
