PARL_HUMAN
ID PARL_HUMAN Reviewed; 379 AA.
AC Q9H300; Q96CQ4; Q9BTJ6; Q9P1E3;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 168.
DE RecName: Full=Presenilins-associated rhomboid-like protein, mitochondrial;
DE EC=3.4.21.105 {ECO:0000269|PubMed:22354088};
DE AltName: Full=Mitochondrial intramembrane cleaving protease PARL;
DE Contains:
DE RecName: Full=P-beta;
DE Short=Pbeta;
DE Flags: Precursor;
GN Name=PARL; Synonyms=PSARL; ORFNames=PRO2207;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT LEU-262, AND INTERACTION
RP WITH PSEN1 AND PSEN2.
RX PubMed=12214059; DOI=10.3233/jad-2001-3203;
RA Pellegrini L., Passer B.J., Canelles M., Lefterov I., Ganjei J.K.,
RA Fowlkes B.J., Koonin E.V., D'Adamio L.;
RT "PAMP and PARL, two novel putative metalloproteases interacting with the
RT COOH-terminus of presenilin-1 and -2.";
RL J. Alzheimers Dis. 3:181-190(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Lung;
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 192-379 (ISOFORM 1), AND VARIANT
RP LEU-262.
RC TISSUE=Fetal liver;
RA Zhang C., Yu Y., Zhang S., Wei H., Zhou G., Ouyang S., Luo L., Bi J.,
RA Liu M., He F.;
RT "Functional prediction of the coding sequences of 121 new genes deduced by
RT analysis of cDNA clones from human fetal liver.";
RL Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP PROTEIN SEQUENCE OF 53-61 AND 78-85, FUNCTION IN BETA CLEAVAGE, AND
RP MUTAGENESIS OF ARG-76; SER-77; ALA-78 AND LEU-79.
RX PubMed=14732705; DOI=10.1074/jbc.m313756200;
RA Sik A., Passer B.J., Koonin E.V., Pellegrini L.;
RT "Self-regulated cleavage of the mitochondrial intramembrane-cleaving
RT protease PARL yields Pbeta, a nuclear-targeted peptide.";
RL J. Biol. Chem. 279:15323-15329(2004).
RN [5]
RP FUNCTION, PHOSPHORYLATION AT SER-65; THR-69 AND SER-70 OF P-BETA,
RP MUTAGENESIS OF SER-65; THR-69 AND SER-70, SUBCELLULAR LOCATION, TOPOLOGY,
RP AND BETA-CLEAVAGE.
RX PubMed=17116872; DOI=10.1073/pnas.0604983103;
RA Jeyaraju D.V., Xu L., Letellier M.-C., Bandaru S., Zunino R., Berg E.A.,
RA McBride H.M., Pellegrini L.;
RT "Phosphorylation and cleavage of presenilin-associated rhomboid-like
RT protein (PARL) promotes changes in mitochondrial morphology.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18562-18567(2006).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=22354088; DOI=10.1038/embor.2012.14;
RA Greene A.W., Grenier K., Aguileta M.A., Muise S., Farazifard R.,
RA Haque M.E., McBride H.M., Park D.S., Fon E.A.;
RT "Mitochondrial processing peptidase regulates PINK1 processing, import and
RT Parkin recruitment.";
RL EMBO Rep. 13:378-385(2012).
CC -!- FUNCTION: Required for the control of apoptosis during postnatal
CC growth. Essential for proteolytic processing of an antiapoptotic form
CC of OPA1 which prevents the release of mitochondrial cytochrome c in
CC response to intrinsic apoptotic signals (By similarity). Required for
CC the maturation of PINK1 into its 52kDa mature form after its cleavage
CC by mitochondrial-processing peptidase (MPP) (PubMed:22354088). Promotes
CC changes in mitochondria morphology regulated by phosphorylation of P-
CC beta domain (PubMed:14732705, PubMed:17116872).
CC {ECO:0000250|UniProtKB:Q5XJY4, ECO:0000269|PubMed:14732705,
CC ECO:0000269|PubMed:17116872, ECO:0000269|PubMed:22354088}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Cleaves type-1 transmembrane domains using a catalytic dyad
CC composed of serine and histidine that are contributed by different
CC transmembrane domains.; EC=3.4.21.105;
CC Evidence={ECO:0000269|PubMed:22354088};
CC -!- SUBUNIT: Interacts with PSEN1 and PSEN2. Binds OPA1.
CC {ECO:0000269|PubMed:12214059}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:17116872, ECO:0000269|PubMed:22354088}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:17116872}.
CC -!- SUBCELLULAR LOCATION: [P-beta]: Nucleus {ECO:0000269|PubMed:17116872}.
CC Note=Translocated into the nucleus by an unknown mechanism
CC (PubMed:17116872). {ECO:0000269|PubMed:17116872}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9H300-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9H300-2; Sequence=VSP_013310;
CC -!- PTM: P-beta is proteolytically processed (beta-cleavage) in a PARL-
CC dependent manner. The cleavage is inhibited when residues Ser-65, Thr-
CC 69 and Ser-70 are all phosphorylated. {ECO:0000269|PubMed:17116872}.
CC -!- SIMILARITY: Belongs to the peptidase S54 family. {ECO:0000305}.
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DR EMBL; AF197937; AAG28519.1; -; mRNA.
DR EMBL; BC003653; AAH03653.1; -; mRNA.
DR EMBL; BC014058; AAH14058.1; -; mRNA.
DR EMBL; AF116692; AAF71112.1; -; mRNA.
DR CCDS; CCDS3248.1; -. [Q9H300-1]
DR CCDS; CCDS33897.1; -. [Q9H300-2]
DR RefSeq; NP_001032728.1; NM_001037639.2. [Q9H300-2]
DR RefSeq; NP_061092.3; NM_018622.6. [Q9H300-1]
DR AlphaFoldDB; Q9H300; -.
DR BioGRID; 120678; 219.
DR IntAct; Q9H300; 181.
DR MINT; Q9H300; -.
DR STRING; 9606.ENSP00000325421; -.
DR MEROPS; S54.009; -.
DR TCDB; 9.B.104.1.6; the rhomboid protease (rhomboid) family.
DR iPTMnet; Q9H300; -.
DR PhosphoSitePlus; Q9H300; -.
DR SwissPalm; Q9H300; -.
DR BioMuta; PARL; -.
DR DMDM; 143811433; -.
DR EPD; Q9H300; -.
DR jPOST; Q9H300; -.
DR MassIVE; Q9H300; -.
DR MaxQB; Q9H300; -.
DR PaxDb; Q9H300; -.
DR PeptideAtlas; Q9H300; -.
DR PRIDE; Q9H300; -.
DR ProteomicsDB; 80637; -. [Q9H300-1]
DR ProteomicsDB; 80638; -. [Q9H300-2]
DR Antibodypedia; 18935; 170 antibodies from 31 providers.
DR DNASU; 55486; -.
DR Ensembl; ENST00000311101.9; ENSP00000310676.5; ENSG00000175193.14. [Q9H300-2]
DR Ensembl; ENST00000317096.9; ENSP00000325421.5; ENSG00000175193.14. [Q9H300-1]
DR GeneID; 55486; -.
DR KEGG; hsa:55486; -.
DR MANE-Select; ENST00000317096.9; ENSP00000325421.5; NM_018622.7; NP_061092.3.
DR UCSC; uc003fmd.4; human. [Q9H300-1]
DR CTD; 55486; -.
DR DisGeNET; 55486; -.
DR GeneCards; PARL; -.
DR HGNC; HGNC:18253; PARL.
DR HPA; ENSG00000175193; Low tissue specificity.
DR MIM; 607858; gene.
DR neXtProt; NX_Q9H300; -.
DR OpenTargets; ENSG00000175193; -.
DR PharmGKB; PA134939789; -.
DR VEuPathDB; HostDB:ENSG00000175193; -.
DR eggNOG; KOG2980; Eukaryota.
DR GeneTree; ENSGT00390000013063; -.
DR HOGENOM; CLU_034022_0_1_1; -.
DR InParanoid; Q9H300; -.
DR OMA; WRCWARA; -.
DR OrthoDB; 1554324at2759; -.
DR PhylomeDB; Q9H300; -.
DR TreeFam; TF313603; -.
DR BRENDA; 3.4.21.105; 2681.
DR PathwayCommons; Q9H300; -.
DR Reactome; R-HSA-8949664; Processing of SMDT1.
DR SignaLink; Q9H300; -.
DR SIGNOR; Q9H300; -.
DR BioGRID-ORCS; 55486; 116 hits in 1081 CRISPR screens.
DR ChiTaRS; PARL; human.
DR GeneWiki; PARL; -.
DR GenomeRNAi; 55486; -.
DR Pharos; Q9H300; Tbio.
DR PRO; PR:Q9H300; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q9H300; protein.
DR Bgee; ENSG00000175193; Expressed in monocyte and 98 other tissues.
DR ExpressionAtlas; Q9H300; baseline and differential.
DR Genevisible; Q9H300; HS.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005743; C:mitochondrial inner membrane; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0004175; F:endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IBA:GO_Central.
DR GO; GO:0033619; P:membrane protein proteolysis; IDA:UniProtKB.
DR GO; GO:0008053; P:mitochondrial fusion; IEA:Ensembl.
DR GO; GO:2001243; P:negative regulation of intrinsic apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; IEA:Ensembl.
DR GO; GO:0006508; P:proteolysis; IMP:ParkinsonsUK-UCL.
DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; IEA:Ensembl.
DR GO; GO:0010821; P:regulation of mitochondrion organization; IMP:ParkinsonsUK-UCL.
DR GO; GO:1903214; P:regulation of protein targeting to mitochondrion; IGI:ParkinsonsUK-UCL.
DR GO; GO:0030162; P:regulation of proteolysis; IGI:ParkinsonsUK-UCL.
DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:ParkinsonsUK-UCL.
DR GO; GO:0006465; P:signal peptide processing; IBA:GO_Central.
DR Gene3D; 1.20.1540.10; -; 1.
DR InterPro; IPR022764; Peptidase_S54_rhomboid_dom.
DR InterPro; IPR035952; Rhomboid-like_sf.
DR Pfam; PF01694; Rhomboid; 1.
DR SUPFAM; SSF144091; SSF144091; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Direct protein sequencing; Hydrolase; Membrane;
KW Mitochondrion; Mitochondrion inner membrane; Nucleus; Phosphoprotein;
KW Protease; Reference proteome; Serine protease; Transit peptide;
KW Transmembrane; Transmembrane helix.
FT TRANSIT 1..52
FT /note="Mitochondrion"
FT /evidence="ECO:0000269|PubMed:14732705"
FT CHAIN 53..379
FT /note="Presenilins-associated rhomboid-like protein,
FT mitochondrial"
FT /id="PRO_0000027386"
FT PEPTIDE 53..77
FT /note="P-beta"
FT /evidence="ECO:0000269|PubMed:14732705"
FT /id="PRO_0000027387"
FT TOPO_DOM 53..101
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000255"
FT TRANSMEM 102..121
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 122..167
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000255"
FT TRANSMEM 168..187
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 188..207
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000255"
FT TRANSMEM 208..230
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 231..244
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000255"
FT TRANSMEM 245..262
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 263..272
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000255"
FT TRANSMEM 273..289
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 290..295
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000255"
FT TRANSMEM 296..318
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 319..332
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000255"
FT TRANSMEM 333..354
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 355..379
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000255"
FT ACT_SITE 277
FT /note="Nucleophile"
FT /evidence="ECO:0000250"
FT ACT_SITE 335
FT /evidence="ECO:0000250"
FT MOD_RES 65
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:17116872"
FT MOD_RES 69
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:17116872"
FT MOD_RES 70
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:17116872"
FT VAR_SEQ 203..253
FT /note="KVLCSPMLLSTFSHFSLFHMAANMYVLWSFSSSIVNILGQEQFMAVYLSAG
FT -> S (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_013310"
FT VARIANT 137
FT /note="A -> G (in dbSNP:rs4912470)"
FT /id="VAR_029801"
FT VARIANT 262
FT /note="V -> L (in dbSNP:rs3732581)"
FT /evidence="ECO:0000269|PubMed:12214059, ECO:0000269|Ref.3"
FT /id="VAR_021578"
FT MUTAGEN 65
FT /note="S->D: Strongly reduces the beta cleavage; when
FT associated with D-69 and D-70."
FT /evidence="ECO:0000269|PubMed:17116872"
FT MUTAGEN 69
FT /note="T->D: Strongly reduces the beta cleavage; when
FT associated with D-65 and D-70."
FT /evidence="ECO:0000269|PubMed:17116872"
FT MUTAGEN 70
FT /note="S->D: Strongly reduces the beta cleavage; when
FT associated with D-65 and D-69."
FT /evidence="ECO:0000269|PubMed:17116872"
FT MUTAGEN 76
FT /note="R->E: Abolishes the beta cleavage."
FT /evidence="ECO:0000269|PubMed:14732705"
FT MUTAGEN 76
FT /note="R->G: Abolishes the beta cleavage."
FT /evidence="ECO:0000269|PubMed:14732705"
FT MUTAGEN 77
FT /note="S->E: Abolishes the beta cleavage."
FT /evidence="ECO:0000269|PubMed:14732705"
FT MUTAGEN 78
FT /note="A->E: Abolishes the beta cleavage."
FT /evidence="ECO:0000269|PubMed:14732705"
FT MUTAGEN 79
FT /note="L->E: Abolishes the beta cleavage."
FT /evidence="ECO:0000269|PubMed:14732705"
SQ SEQUENCE 379 AA; 42190 MW; 2B07EF04C7130B0B CRC64;
MAWRGWAQRG WGCGQAWGAS VGGRSCEELT AVLTPPQLLG RRFNFFIQQK CGFRKAPRKV
EPRRSDPGTS GEAYKRSALI PPVEETVFYP SPYPIRSLIK PLFFTVGFTG CAFGSAAIWQ
YESLKSRVQS YFDGIKADWL DSIRPQKEGD FRKEINKWWN NLSDGQRTVT GIIAANVLVF
CLWRVPSLQR TMIRYFTSNP ASKVLCSPML LSTFSHFSLF HMAANMYVLW SFSSSIVNIL
GQEQFMAVYL SAGVISNFVS YVGKVATGRY GPSLGASGAI MTVLAAVCTK IPEGRLAIIF
LPMFTFTAGN ALKAIIAMDT AGMILGWKFF DHAAHLGGAL FGIWYVTYGH ELIWKNREPL
VKIWHEIRTN GPKKGGGSK
