ATG4D_DANRE
ID ATG4D_DANRE Reviewed; 485 AA.
AC R4GER2;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 20-JUN-2018, sequence version 1.
DT 03-AUG-2022, entry version 23.
DE RecName: Full=Cysteine protease atg4da {ECO:0000305};
DE EC=3.4.22.- {ECO:0000250|UniProtKB:Q86TL0};
DE AltName: Full=Autophagy-related protein 4 homolog D-A {ECO:0000250|UniProtKB:Q86TL0};
GN Name=atg4da {ECO:0000312|ZFIN:ZDB-GENE-041111-102};
GN Synonyms=si:ch211-212h16.5 {ECO:0000312|ZFIN:ZDB-GENE-041111-102};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [2]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=25875846; DOI=10.1371/journal.pgen.1005169;
RA Kyoestilae K., Syrjae P., Jagannathan V., Chandrasekar G., Jokinen T.S.,
RA Seppaelae E.H., Becker D., Droegemueller M., Dietschi E., Droegemueller C.,
RA Lang J., Steffen F., Rohdin C., Jaederlund K.H., Lappalainen A.K., Hahn K.,
RA Wohlsein P., Baumgaertner W., Henke D., Oevermann A., Kere J., Lohi H.,
RA Leeb T.;
RT "A missense change in the ATG4D gene links aberrant autophagy to a
RT neurodegenerative vacuolar storage disease.";
RL PLoS Genet. 11:e1005169-e1005169(2015).
CC -!- FUNCTION: Cysteine protease that plays a key role in autophagy by
CC mediating both proteolytic activation and delipidation of ATG8 family
CC proteins (By similarity). The protease activity is required for
CC proteolytic activation of ATG8 family proteins to reveal a C-terminal
CC glycine (By similarity). Exposure of the glycine at the C-terminus is
CC essential for ATG8 proteins conjugation to phosphatidylethanolamine
CC (PE) and insertion to membranes, which is necessary for autophagy (By
CC similarity). In addition to the protease activity, also mediates
CC delipidation of ATG8 family proteins. Catalyzes delipidation of PE-
CC conjugated forms of ATG8 proteins during macroautophagy (By
CC similarity). Also involved in non-canonical autophagy, a parallel
CC pathway involving conjugation of ATG8 proteins to single membranes at
CC endolysosomal compartments, by catalyzing delipidation of ATG8 proteins
CC conjugated to phosphatidylserine (PS) (By similarity). ATG4D plays a
CC role in the autophagy-mediated neuronal homeostasis in the central
CC nervous system (PubMed:25875846). {ECO:0000250|UniProtKB:Q86TL0,
CC ECO:0000250|UniProtKB:Q9Y4P1, ECO:0000269|PubMed:25875846}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-C-terminal L-amino acid-glycyl-
CC phosphatidylethanolamide + H2O = [protein]-C-terminal L-amino acid-
CC glycine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine;
CC Xref=Rhea:RHEA:67548, Rhea:RHEA-COMP:17323, Rhea:RHEA-COMP:17324,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:64612, ChEBI:CHEBI:172940,
CC ChEBI:CHEBI:172941; Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549;
CC Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-C-terminal L-amino acid-glycyl-phosphatidylserine +
CC H2O = [protein]-C-terminal L-amino acid-glycine + a 1,2-diacyl-sn-
CC glycero-3-phospho-L-serine; Xref=Rhea:RHEA:67576, Rhea:RHEA-
CC COMP:17324, Rhea:RHEA-COMP:17326, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:57262, ChEBI:CHEBI:172940, ChEBI:CHEBI:172942;
CC Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67577;
CC Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- DISRUPTION PHENOTYPE: Morpholino knockdown of the protein results in
CC neurodegeneration in the central nervous system (CNS)
CC (PubMed:25875846). Neurodegeneration is characterized by severe visible
CC malformations in the developing CNS in regions that correspond to the
CC midbrain-hindbrain boundary, the cerebellum and the hindbrain region
CC (PubMed:25875846). {ECO:0000269|PubMed:25875846}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
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DR EMBL; BX547996; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; XP_009292711.1; XM_009294436.2.
DR RefSeq; XP_009292712.1; XM_009294437.2.
DR AlphaFoldDB; R4GER2; -.
DR SMR; R4GER2; -.
DR STRING; 7955.ENSDARP00000126975; -.
DR Ensembl; ENSDART00000152289; ENSDARP00000126975; ENSDARG00000043548.
DR GeneID; 795933; -.
DR KEGG; dre:795933; -.
DR CTD; 795933; -.
DR ZFIN; ZDB-GENE-041111-102; atg4da.
DR GeneTree; ENSGT00530000063000; -.
DR OMA; MPRDWAW; -.
DR Reactome; R-DRE-1632852; Macroautophagy.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 1.
DR Bgee; ENSDARG00000043548; Expressed in early embryo and 21 other tissues.
DR ExpressionAtlas; R4GER2; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0098749; P:cerebellar neuron development; IMP:ZFIN.
DR GO; GO:0021702; P:cerebellar Purkinje cell differentiation; IMP:ZFIN.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR005078; Peptidase_C54.
DR PANTHER; PTHR22624; PTHR22624; 1.
DR Pfam; PF03416; Peptidase_C54; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
PE 3: Inferred from homology;
KW Autophagy; Cytoplasm; Hydrolase; Protease; Protein transport;
KW Reference proteome; Thiol protease; Transport.
FT CHAIN 1..485
FT /note="Cysteine protease atg4da"
FT /id="PRO_0000454237"
FT REGION 22..46
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 131
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 368
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 370
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
SQ SEQUENCE 485 AA; 53363 MW; 42747E863B898E5A CRC64;
MNSVSPSAVQ YIVGGGAHED KASASSKRHL GHGAVPDGIR EGSGEPDEVD RLKAKFMSAW
NNVKYGWTVK SKTSFNKSSP LILLGQSFLF NNEDEVERFR QTFVSCVWLT YRREFPQLDG
SSLTTDCGWG CMLRSGQMML AQGLLLHLMP TDWRWSDCHA LTDVDFEVLK PRSPSRPAGM
SMPSFSSSWS SSIPQINPSP GITEAHRRAP ARCPSASPDP QVDALHRKVV SCFGDHPSAP
FGVHQLVELG KESGKRAGDW YGPSVVAHML RKAVARAAEF EDLAVYVAQD CTVYKEDVMS
LCESSGVGWK SVVILVPVRL GGESLNPSYI ECVKNILKLK CCIGIIGGKP KHSLFFVGFQ
DEQLLYLDPH YCQPVVDVTQ ANFSLESFHC NSPRKMNFSR MDPSCTIGLY ARSKTDFESL
CTAVSEALSS SKEKYPIFTF VEGRGQIYGM EGPSGGSVDA PAHIFTCSRL SRNNKRGSTD
EFVLL
