ATG4D_CANLF
ID ATG4D_CANLF Reviewed; 473 AA.
AC E2RDP2;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 1.
DT 03-AUG-2022, entry version 71.
DE RecName: Full=Cysteine protease ATG4D {ECO:0000305};
DE EC=3.4.22.- {ECO:0000250|UniProtKB:Q86TL0};
DE AltName: Full=Autophagy-related protein 4 homolog D {ECO:0000250|UniProtKB:Q86TL0};
DE Contains:
DE RecName: Full=Cysteine protease ATG4D, mitochondrial {ECO:0000250|UniProtKB:Q86TL0};
GN Name=ATG4D;
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Boxer;
RX PubMed=16341006; DOI=10.1038/nature04338;
RA Lindblad-Toh K., Wade C.M., Mikkelsen T.S., Karlsson E.K., Jaffe D.B.,
RA Kamal M., Clamp M., Chang J.L., Kulbokas E.J. III, Zody M.C., Mauceli E.,
RA Xie X., Breen M., Wayne R.K., Ostrander E.A., Ponting C.P., Galibert F.,
RA Smith D.R., deJong P.J., Kirkness E.F., Alvarez P., Biagi T., Brockman W.,
RA Butler J., Chin C.-W., Cook A., Cuff J., Daly M.J., DeCaprio D., Gnerre S.,
RA Grabherr M., Kellis M., Kleber M., Bardeleben C., Goodstadt L., Heger A.,
RA Hitte C., Kim L., Koepfli K.-P., Parker H.G., Pollinger J.P.,
RA Searle S.M.J., Sutter N.B., Thomas R., Webber C., Baldwin J., Abebe A.,
RA Abouelleil A., Aftuck L., Ait-Zahra M., Aldredge T., Allen N., An P.,
RA Anderson S., Antoine C., Arachchi H., Aslam A., Ayotte L., Bachantsang P.,
RA Barry A., Bayul T., Benamara M., Berlin A., Bessette D., Blitshteyn B.,
RA Bloom T., Blye J., Boguslavskiy L., Bonnet C., Boukhgalter B., Brown A.,
RA Cahill P., Calixte N., Camarata J., Cheshatsang Y., Chu J., Citroen M.,
RA Collymore A., Cooke P., Dawoe T., Daza R., Decktor K., DeGray S.,
RA Dhargay N., Dooley K., Dooley K., Dorje P., Dorjee K., Dorris L.,
RA Duffey N., Dupes A., Egbiremolen O., Elong R., Falk J., Farina A., Faro S.,
RA Ferguson D., Ferreira P., Fisher S., FitzGerald M., Foley K., Foley C.,
RA Franke A., Friedrich D., Gage D., Garber M., Gearin G., Giannoukos G.,
RA Goode T., Goyette A., Graham J., Grandbois E., Gyaltsen K., Hafez N.,
RA Hagopian D., Hagos B., Hall J., Healy C., Hegarty R., Honan T., Horn A.,
RA Houde N., Hughes L., Hunnicutt L., Husby M., Jester B., Jones C., Kamat A.,
RA Kanga B., Kells C., Khazanovich D., Kieu A.C., Kisner P., Kumar M.,
RA Lance K., Landers T., Lara M., Lee W., Leger J.-P., Lennon N., Leuper L.,
RA LeVine S., Liu J., Liu X., Lokyitsang Y., Lokyitsang T., Lui A.,
RA Macdonald J., Major J., Marabella R., Maru K., Matthews C., McDonough S.,
RA Mehta T., Meldrim J., Melnikov A., Meneus L., Mihalev A., Mihova T.,
RA Miller K., Mittelman R., Mlenga V., Mulrain L., Munson G., Navidi A.,
RA Naylor J., Nguyen T., Nguyen N., Nguyen C., Nguyen T., Nicol R., Norbu N.,
RA Norbu C., Novod N., Nyima T., Olandt P., O'Neill B., O'Neill K., Osman S.,
RA Oyono L., Patti C., Perrin D., Phunkhang P., Pierre F., Priest M.,
RA Rachupka A., Raghuraman S., Rameau R., Ray V., Raymond C., Rege F.,
RA Rise C., Rogers J., Rogov P., Sahalie J., Settipalli S., Sharpe T.,
RA Shea T., Sheehan M., Sherpa N., Shi J., Shih D., Sloan J., Smith C.,
RA Sparrow T., Stalker J., Stange-Thomann N., Stavropoulos S., Stone C.,
RA Stone S., Sykes S., Tchuinga P., Tenzing P., Tesfaye S., Thoulutsang D.,
RA Thoulutsang Y., Topham K., Topping I., Tsamla T., Vassiliev H.,
RA Venkataraman V., Vo A., Wangchuk T., Wangdi T., Weiand M., Wilkinson J.,
RA Wilson A., Yadav S., Yang S., Yang X., Young G., Yu Q., Zainoun J.,
RA Zembek L., Zimmer A., Lander E.S.;
RT "Genome sequence, comparative analysis and haplotype structure of the
RT domestic dog.";
RL Nature 438:803-819(2005).
RN [2]
RP FUNCTION, INVOLVEMENT IN NEURODEGENERATIVE DISEASE, AND VARIANT THR-430.
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 ATG4D]: Cysteine protease that plays a key
CC role in autophagy by mediating both proteolytic activation and
CC delipidation of ATG8 family proteins. The protease activity is required
CC for proteolytic activation of ATG8 family proteins: cleaves the C-
CC terminal amino acid of ATG8 proteins MAP1LC3 and GABARAPL2, to reveal a
CC C-terminal glycine (By similarity). Exposure of the glycine at the C-
CC terminus is essential for ATG8 proteins conjugation to
CC phosphatidylethanolamine (PE) and insertion to membranes, which is
CC necessary for autophagy (By similarity). In addition to the protease
CC activity, also mediates delipidation of ATG8 family proteins. Catalyzes
CC delipidation of PE-conjugated forms of ATG8 proteins during
CC macroautophagy. 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). Compared to other members of the
CC family (ATG4A, ATG4B or ATG4C), constitutes the major protein for the
CC delipidation activity, while it promotes weak proteolytic activation of
CC ATG8 proteins (By similarity). Involved in phagophore growth during
CC mitophagy independently of its protease activity and of ATG8 proteins:
CC acts by regulating ATG9A trafficking to mitochondria and promoting
CC phagophore-endoplasmic reticulum contacts during the lipid transfer
CC phase of mitophagy (By similarity). {ECO:0000250|UniProtKB:Q86TL0,
CC ECO:0000250|UniProtKB:Q8BGV9, ECO:0000250|UniProtKB:Q9Y4P1,
CC ECO:0000269|PubMed:25875846}.
CC -!- FUNCTION: [Cysteine protease ATG4D, mitochondrial]: Plays a role as an
CC autophagy regulator that links mitochondrial dysfunction with
CC apoptosis. The mitochondrial import of ATG4D during cellular stress and
CC differentiation may play important roles in the regulation of
CC mitochondrial physiology, ROS, mitophagy and cell viability.
CC {ECO:0000250|UniProtKB:Q86TL0}.
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 -!- ACTIVITY REGULATION: Inhibited by N-ethylmaleimide.
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- SUBCELLULAR LOCATION: [Cysteine protease ATG4D]: Cytoplasm
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- SUBCELLULAR LOCATION: [Cysteine protease ATG4D, mitochondrial]:
CC Cytoplasm {ECO:0000250|UniProtKB:Q86TL0}. Mitochondrion matrix
CC {ECO:0000250|UniProtKB:Q86TL0}. Note=Imported into mitochondrial matrix
CC after cleavage by CASP3 during oxidative stress and cell death.
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- DOMAIN: The cryptic mitochondrial transit peptide is revealed after
CC cleavage by caspase upon oxidative stress and cell death. It acts then
CC as a functional transit peptide, and allows the import of the cleaved
CC protein into the mitochondria. {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- PTM: Cleaved by CASP3 during apoptosis which leads to increased
CC activity. The cleavage by CASP3 reveals a cryptic mitochondrial
CC targeting sequence immediately downstream of their canonical caspase
CC cleavage sites which leads to mitochondrial import of the protein.
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- DISEASE: Note=Defects in ATG4D are the cause of a neurodegenerative
CC disease present in the Lagotto Romagnolo dog breed (PubMed:25875846).
CC Affected dogs suffer from progressive cerebellar ataxia, sometimes
CC accompanied by episodic nystagmus and behavioral changes
CC (PubMed:25875846). Defects are caused by impaired autophagy: neuronal
CC cells display cytoplasmic vacuolization in the nervous system, as well
CC as spheroid formation and cytoplasmic aggregation of vacuoles in
CC secretory epithelial tissues and mesenchymal cells (PubMed:25875846).
CC {ECO:0000269|PubMed:25875846}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
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DR EMBL; AAEX03012418; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AAEX03012419; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; XP_542069.1; XM_542069.5.
DR SMR; E2RDP2; -.
DR STRING; 9612.ENSCAFP00000026214; -.
DR MEROPS; C54.005; -.
DR PaxDb; E2RDP2; -.
DR Ensembl; ENSCAFT00030035500; ENSCAFP00030030961; ENSCAFG00030019316.
DR Ensembl; ENSCAFT00040037370; ENSCAFP00040032567; ENSCAFG00040020210.
DR Ensembl; ENSCAFT00845046627; ENSCAFP00845036604; ENSCAFG00845026379.
DR GeneID; 484953; -.
DR CTD; 84971; -.
DR VEuPathDB; HostDB:ENSCAFG00845026379; -.
DR eggNOG; KOG2674; Eukaryota.
DR GeneTree; ENSGT00530000063000; -.
DR HOGENOM; CLU_021259_3_2_1; -.
DR InParanoid; E2RDP2; -.
DR OMA; PMEATHR; -.
DR OrthoDB; 431748at2759; -.
DR TreeFam; TF314847; -.
DR Reactome; R-CFA-1632852; Macroautophagy.
DR Proteomes; UP000002254; Chromosome 20.
DR Bgee; ENSCAFG00000017776; Expressed in granulocyte and 49 other tissues.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0000423; P:mitophagy; IEA:Ensembl.
DR GO; GO:0051697; P:protein delipidation; IEA:Ensembl.
DR GO; GO:0034497; P:protein localization to phagophore assembly site; IEA:Ensembl.
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 Apoptosis; Autophagy; Cytoplasm; Hydrolase; Mitochondrion; Phosphoprotein;
KW Protease; Protein transport; Reference proteome; Thiol protease; Transport;
KW Ubl conjugation pathway.
FT CHAIN 1..473
FT /note="Cysteine protease ATG4D"
FT /id="PRO_0000454235"
FT CHAIN 63..473
FT /note="Cysteine protease ATG4D, mitochondrial"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT /id="PRO_0000454236"
FT REGION 1..59
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 63..102
FT /note="Cryptic mitochondrial signal peptide"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT COMPBIAS 16..32
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 143
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 355
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 357
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT SITE 62..63
FT /note="Cleavage; by CASP3"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT MOD_RES 466
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT VARIANT 430
FT /note="A -> T (found in dogs with neurodegenerative
FT disease)"
FT /evidence="ECO:0000269|PubMed:25875846"
SQ SEQUENCE 473 AA; 52747 MW; 50424FA7AC1AD4E8 CRC64;
MNSVSPAAAQ YRSGSPEDAR RPEGRRPRGP RVPDPNGPRP SGASGPALGS PAAAPGEPDE
VDKFKAKFLT AWNNVKYGWA VKSRTSFSKI SSVHLCGRRY RFEGEGDIQR FQRDFVSRLW
LTYRRDFPPL AGGCLTSDCG WGCMLRSGQM MLAQGLLLHF LPRDWTWAEG PGLGPSEPAG
LASPNRYRGP ARWMPPRWAQ GTPELEQERR HRQIVSWFAD HPQAPFGLHR LVELGQSSGK
KAGDWYGPSL VAHILRKAVE SCSEITRLVV YVSQDCTVYK ADVARLVARP DPTAEWKSVV
ILVPVRLGGE TLNPVYVPCV KELLRSELCL GIMGGKPRHS LYFIGYQDDF LLYLDPHYCQ
PTVDVSQADF PLESFHCTSP RKMAFAKMDP SCTVGFYAGD QKEFETLCSE LTRVLSSSSA
TERYPMFTLA EGHAQDHSLD DLCSQLSQPT LRLPRTGRLL KAKRPSSEDF VFL
