MADD_RAT
ID MADD_RAT Reviewed; 1602 AA.
AC O08873;
DT 20-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1997, sequence version 1.
DT 03-AUG-2022, entry version 125.
DE RecName: Full=MAP kinase-activating death domain protein;
DE AltName: Full=Rab3 GDP/GTP exchange factor;
DE Short=RabGEF {ECO:0000305};
DE AltName: Full=Rab3 GDP/GTP exchange protein {ECO:0000305};
DE Short=RabGEP {ECO:0000305};
GN Name=Madd {ECO:0000312|RGD:619922};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1] {ECO:0000305, ECO:0000312|EMBL:AAC53149.1}
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 2-23; 119-138; 680-699;
RP 748-766; 905-920; 962-985; 1061-1083; 1106-1116; 1222-1248 AND 1493-1507,
RP FUNCTION, AND TISSUE SPECIFICITY.
RC TISSUE=Brain {ECO:0000269|PubMed:9020086};
RX PubMed=9020086; DOI=10.1074/jbc.272.7.3875;
RA Wada M., Nakanishi H., Satoh A., Hirano H., Obaishi H., Matsuura Y.,
RA Takai Y.;
RT "Isolation and characterization of a GDP/GTP exchange protein specific for
RT the Rab3 subfamily small G proteins.";
RL J. Biol. Chem. 272:3875-3878(1997).
RN [2] {ECO:0000305}
RP DISRUPTION PHENOTYPE.
RX PubMed=15007167; DOI=10.1073/pnas.0307349101;
RA Del Villar K., Miller C.A.;
RT "Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates
RT with neuronal cell death in Alzheimer's disease brain and hippocampal
RT neurons.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:4210-4215(2004).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-812, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=16641100; DOI=10.1073/pnas.0600895103;
RA Hoffert J.D., Pisitkun T., Wang G., Shen R.-F., Knepper M.A.;
RT "Quantitative phosphoproteomics of vasopressin-sensitive renal cells:
RT regulation of aquaporin-2 phosphorylation at two sites.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:7159-7164(2006).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688; SER-691; SER-778;
RP SER-812; SER-909; SER-1038; THR-1040; THR-1045 AND SER-1196, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Guanyl-nucleotide exchange factor that regulates small
CC GTPases of the Rab family (PubMed:9020086). Converts GDP-bound inactive
CC form of RAB27A and RAB27B to the GTP-bound active forms (By
CC similarity). Converts GDP-bound inactive form of RAB3A, RAB3C and RAB3D
CC to the GTP-bound active forms, GTPases involved in synaptic vesicle
CC exocytosis and vesicle secretion (PubMed:9020086). Plays a role in
CC synaptic vesicle formation and in vesicle trafficking at the
CC neuromuscular junction (By similarity). Involved in up-regulating a
CC post-docking step of synaptic exocytosis in central synapses (By
CC similarity). Probably by binding to the motor proteins KIF1B and KIF1A,
CC mediates motor-dependent transport of GTP-RAB3A-positive vesicles to
CC the presynaptic nerve terminals (By similarity). Plays a role in TNFA-
CC mediated activation of the MAPK pathway, including ERK1/2 (By
CC similarity). May link TNFRSF1A with MAP kinase activation (By
CC similarity). May be involved in the regulation of TNFA-induced
CC apoptosis (By similarity). {ECO:0000250|UniProtKB:Q80U28,
CC ECO:0000250|UniProtKB:Q8WXG6, ECO:0000269|PubMed:9020086}.
CC -!- SUBUNIT: Interacts (via death domain) with TNFRSF1A (via death domain)
CC (By similarity). Interacts with PIDD1 (By similarity). Interacts with
CC YWHAZ (By similarity). Interacts (via death domain) with KIF1B (By
CC similarity). Interacts with KIF1A (By similarity). Interacts (via uDENN
CC domain) with RAB3A, RAB3B, RAB3C and RAB3D; the GTP-bound form of the
CC Rab proteins is preferred for interaction (By similarity).
CC {ECO:0000250|UniProtKB:Q80U28, ECO:0000250|UniProtKB:Q8WXG6}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q8WXG6}.
CC Cytoplasm {ECO:0000250|UniProtKB:Q8WXG6}. Cell projection, axon
CC {ECO:0000250|UniProtKB:Q80U28}.
CC -!- TISSUE SPECIFICITY: Expressed in all tissues examined with the highest
CC expression in brain. {ECO:0000269|PubMed:9020086}.
CC -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown in hippocampal cells
CC leads to neuronal cell death. {ECO:0000269|PubMed:15007167}.
CC -!- SIMILARITY: Belongs to the MADD family. {ECO:0000305}.
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DR EMBL; U72995; AAC53149.1; -; mRNA.
DR PIR; T31671; T31671.
DR RefSeq; NP_446037.1; NM_053585.1.
DR AlphaFoldDB; O08873; -.
DR BioGRID; 250173; 5.
DR IntAct; O08873; 1.
DR MINT; O08873; -.
DR STRING; 10116.ENSRNOP00000017360; -.
DR iPTMnet; O08873; -.
DR PhosphoSitePlus; O08873; -.
DR jPOST; O08873; -.
DR PaxDb; O08873; -.
DR PRIDE; O08873; -.
DR GeneID; 94193; -.
DR KEGG; rno:94193; -.
DR UCSC; RGD:619922; rat.
DR CTD; 8567; -.
DR RGD; 619922; Madd.
DR VEuPathDB; HostDB:ENSRNOG00000012568; -.
DR eggNOG; KOG3570; Eukaryota.
DR InParanoid; O08873; -.
DR OrthoDB; 162625at2759; -.
DR PhylomeDB; O08873; -.
DR Reactome; R-RNO-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-RNO-8876198; RAB GEFs exchange GTP for GDP on RABs.
DR PRO; PR:O08873; -.
DR Proteomes; UP000002494; Chromosome 3.
DR Bgee; ENSRNOG00000012568; Expressed in frontal cortex and 20 other tissues.
DR ExpressionAtlas; O08873; baseline and differential.
DR Genevisible; O08873; RN.
DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0016021; C:integral component of membrane; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0045202; C:synapse; IDA:RGD.
DR GO; GO:0008021; C:synaptic vesicle; IDA:RGD.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IDA:RGD.
DR GO; GO:0048490; P:anterograde synaptic vesicle transport; ISO:RGD.
DR GO; GO:0097194; P:execution phase of apoptosis; ISO:RGD.
DR GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; ISO:RGD.
DR GO; GO:0060125; P:negative regulation of growth hormone secretion; IDA:RGD.
DR GO; GO:1902277; P:negative regulation of pancreatic amylase secretion; IMP:RGD.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; ISO:RGD.
DR GO; GO:0051726; P:regulation of cell cycle; ISS:UniProtKB.
DR GO; GO:2001236; P:regulation of extrinsic apoptotic signaling pathway; ISO:RGD.
DR GO; GO:1902041; P:regulation of extrinsic apoptotic signaling pathway via death domain receptors; ISS:UniProtKB.
DR GO; GO:0032483; P:regulation of Rab protein signal transduction; ISO:RGD.
DR Gene3D; 3.40.50.11500; -; 1.
DR InterPro; IPR001194; cDENN_dom.
DR InterPro; IPR005112; dDENN_dom.
DR InterPro; IPR043153; DENN_C.
DR InterPro; IPR039980; MADD.
DR InterPro; IPR037516; Tripartite_DENN.
DR InterPro; IPR005113; uDENN_dom.
DR PANTHER; PTHR13008; PTHR13008; 1.
DR Pfam; PF02141; DENN; 1.
DR Pfam; PF03456; uDENN; 1.
DR SMART; SM00801; dDENN; 1.
DR SMART; SM00799; DENN; 1.
DR SMART; SM00800; uDENN; 1.
DR PROSITE; PS50211; DENN; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Cell membrane; Cell projection; Cytoplasm;
KW Direct protein sequencing; Guanine-nucleotide releasing factor; Membrane;
KW Phosphoprotein; Reference proteome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:9020086"
FT CHAIN 2..1602
FT /note="MAP kinase-activating death domain protein"
FT /evidence="ECO:0000269|PubMed:9020086"
FT /id="PRO_0000278140"
FT DOMAIN 13..267
FT /note="uDENN"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00304"
FT DOMAIN 288..428
FT /note="cDENN"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00304"
FT DOMAIN 430..564
FT /note="dDENN"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00304"
FT DOMAIN 1295..1370
FT /note="Death"
FT /evidence="ECO:0000255"
FT REGION 105..167
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 603..635
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 676..840
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 870..920
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1030..1089
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1113..1231
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 130..155
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 688..714
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 748..762
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 792..807
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 816..840
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1120..1172
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1189..1211
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 155
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8WXG6"
FT MOD_RES 688
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 691
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 778
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 812
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16641100,
FT ECO:0007744|PubMed:22673903"
FT MOD_RES 817
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8WXG6"
FT MOD_RES 819
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8WXG6"
FT MOD_RES 857
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8WXG6"
FT MOD_RES 861
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8WXG6"
FT MOD_RES 895
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8WXG6"
FT MOD_RES 900
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8WXG6"
FT MOD_RES 909
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1038
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1040
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1045
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1089
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q80U28"
FT MOD_RES 1194
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8WXG6"
FT MOD_RES 1196
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1225
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8WXG6"
SQ SEQUENCE 1602 AA; 177992 MW; 3A5071DE637B2A56 CRC64;
MVQKKFCPRL LDYLVIVGAR HPSSDSVAQT PELLRRYPLE DHPEFPLPPD VVFFCQPEGC
LSVRQRRMSL RDDTSFVFTL TDKDTGVTRY GICVNFYRSF QKRMPKEKAE GGAGPRGKEG
AHAPCASEEA ATESSESGST LQPPSADSTP DVNQSPRGKR RAKAGNRSRN STLTSLCVLS
HYPFFSTFRE CLYTLKRLVD CCSERLLGKK PGIPRGVQRD TMWRIFTGSL LVEEKSSALL
HDLREIEAWI YRLLRSPVPV SGQKRVDIEV LPQEVQQALT FALPDPSRFT LVDFPLHLPL
ELLGVDACLQ VLTCILLEHK VVLQSRDYNA LSMSVMAFVA MIYPLEYMFP VIPLLPTCMA
SAEQLLLAPT PYIIGVPASF FLYKLDFKMP DDVWLVDLDS NRVIAPTNAE VLPILPEPES
LELKKHLKQA LASMSLNTQP ILNLEKFHEG QETPLLLGRF SNDLQSTPST EFNPLIYGND
VDSVDVATRV AMVRFFNSAN VLQGFQMHTR TLRLFPRPVV AFQAGSFLAS RPRQTPFAEK
LARTQAVEYF GEWILNPSNY AFQRIHNNTF DPALIGDKPK WYAHQLQPIH YRVYDSNSQL
AEALSVPPER DSESDPTDDS GSDSMDYDDS SSSYSSLGDF VSEMMKCDIN GDTPNVDPLT
HAALGDASEV EIDELQPQKE GEEPGPDSEN SQENLPLRSS SSTTASSSPS TIVHGAHSEP
ADSTEVGDKA ATGISKPLPP VPPSICKSTV DRRQTETGEG SVCQRTYDHP YFEPQYGSPA
EEDDDEQGES YTPRFSQHAS GSRAQKLLRP NSLKLASDSD AESDSRASSP NSTVSNNSTE
GFGGIMSFAS SLYRNHSTSF SLSNLTLPTK GAREKTTPFP SLKGNRRALV DQKSSVIKHS
PTVKREPPSP QGRSSNSSEN QQFLKEVVHS VLDGQGVGWL NMKKVRRLLE SEQLRVFVLS
KLSRAVQSED DARQDVIQDV EISRKVYKGM LDLLKCTVLS LEQSYAHAGL GGMASIFGLL
EIAQTHYYSK EPDKRKRSPT ENVNTPVGKD PGLAGRGDPK AMAQLRVPQL GPRAPSATGR
GPKELDTRSL KEENFVASVG PEVIKPVFDL GETEEKKSQI SADSGVSLAS ASQRTDQDSV
IGVSPAVMIR SSSQDSEVSN SSGETLGADS DLSSNAGDGP GGEGSAHLAS SRATLSDSEI
ETNSATSTIF GKAHSLKPKE KPASSPVRSS EDVSQRVYLY EGLLGRDKGS MWDQLEDAAM
ETFSISKERS TLWDQMQFWE DAFLDAVMLE REGMGMDQGP QEMIDRYLSL GEHDRKRLED
DEDRLLATLL HNLISYMLLM KVNKNDIRKK VRRLMGKSHV GLVYSQQINE VLDQLTNLNG
RDLSIRSSGS RHMKKQTFVV HAGTDTNGDI FFMEVCDDCV VLRSNIGTVY ERWWYEKLIN
MTYCPKTKVL CLWRRNGSET QLNKFYTKKC RELYYCVKDS MERAAARQQS IKPGPELGGE
FPVQDMKTGE GGLLQVTLEG INLKFMHNQV FIELNHIKKC NTVRGVFVLE EFVPEIKEVV
SHKYKTPMAH EICYSVLCLF SYVAAVRSSE EDLRTPPRPV SS
