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   27-MAR-2024, entry version 177.
DE   RecName: Full=Presenilin-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).
RN   [7]
RP   FUNCTION, AND MUTAGENESIS OF SER-277 AND HIS-335.
RX   PubMed=22915595; DOI=10.1074/jbc.m112.357509;
RA   Sekine S., Kanamaru Y., Koike M., Nishihara A., Okada M., Kinoshita H.,
RA   Kamiyama M., Maruyama J., Uchiyama Y., Ishihara N., Takeda K., Ichijo H.;
RT   "Rhomboid protease PARL mediates the mitochondrial membrane potential loss-
RT   induced cleavage of PGAM5.";
RL   J. Biol. Chem. 287:34635-34645(2012).
RN   [8]
RP   FUNCTION, AND MUTAGENESIS OF SER-277.
RX   PubMed=28288130; DOI=10.1038/ncb3488;
RA   Saita S., Nolte H., Fiedler K.U., Kashkar H., Venne A.S., Zahedi R.P.,
RA   Krueger M., Langer T.;
RT   "PARL mediates Smac proteolytic maturation in mitochondria to promote
RT   apoptosis.";
RL   Nat. Cell Biol. 19:318-328(2017).
RN   [9]
RP   FUNCTION.
RX   PubMed=32573439; DOI=10.7554/elife.55279;
RA   Cupo R.R., Shorter J.;
RT   "Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is
RT   inactivated by 3-methylglutaconic aciduria-linked mutations.";
RL   Elife 9:0-0(2020).
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       cleavage of serine/threonine-protein phosphatase PGAM5 in damaged
CC       mitochondria in response to loss of mitochondrial membrane potential
CC       (PubMed:22915595). Mediates differential cleavage of PINK1 and PGAM5
CC       depending on the health status of mitochondria, disassociating from
CC       PINK1 and associating with PGAM5 in response to mitochondrial membrane
CC       potential loss (PubMed:22915595). Required for processing of CLPB into
CC       a form with higher protein disaggregase activity by removing an
CC       autoinhibitory N-terminal peptide (PubMed:28288130, PubMed:32573439).
CC       Promotes processing of DIABLO/SMAC in the mitochondrion which is
CC       required for DIABLO apoptotic activity (PubMed:28288130). Also required
CC       for cleavage of STARD7 and TTC19 (PubMed:28288130). Promotes changes in
CC       mitochondria morphology regulated by phosphorylation of P-beta domain
CC       (PubMed:14732705, PubMed:17116872). {ECO:0000250|UniProtKB:Q5XJY4,
CC       ECO:0000269|PubMed:14732705, ECO:0000269|PubMed:17116872,
CC       ECO:0000269|PubMed:22354088, ECO:0000269|PubMed:22915595,
CC       ECO:0000269|PubMed:28288130, ECO:0000269|PubMed:32573439}.
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   SMR; Q9H300; -.
DR   BioGRID; 120678; 222.
DR   IntAct; Q9H300; 181.
DR   MINT; Q9H300; -.
DR   STRING; 9606.ENSP00000325421; -.
DR   BindingDB; Q9H300; -.
DR   ChEMBL; CHEMBL4879516; -.
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; 9606-ENSP00000325421; -.
DR   PeptideAtlas; Q9H300; -.
DR   ProteomicsDB; 80637; -. [Q9H300-1]
DR   ProteomicsDB; 80638; -. [Q9H300-2]
DR   Pumba; Q9H300; -.
DR   Antibodypedia; 18935; 184 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   AGR; HGNC:18253; -.
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; WHEMRTR; -.
DR   OrthoDB; 2910971at2759; -.
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; 131 hits in 1160 CRISPR screens.
DR   ChiTaRS; PARL; human.
DR   GeneWiki; PARL; -.
DR   GenomeRNAi; 55486; -.
DR   Pharos; Q9H300; Tchem.
DR   PRO; PR:Q9H300; -.
DR   Proteomes; UP000005640; Chromosome 3.
DR   RNAct; Q9H300; Protein.
DR   Bgee; ENSG00000175193; Expressed in monocyte and 100 other cell types or tissues.
DR   ExpressionAtlas; Q9H300; baseline and differential.
DR   GO; GO:0005743; C:mitochondrial inner membrane; TAS:ParkinsonsUK-UCL.
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; IMP:UniProtKB.
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:0016485; P:protein processing; IMP:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0010821; P:regulation of mitochondrion organization; IMP:ParkinsonsUK-UCL.
DR   GO; GO:1901524; P:regulation of mitophagy; ISS: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; Rhomboid-like; 1.
DR   InterPro; IPR022764; Peptidase_S54_rhomboid_dom.
DR   InterPro; IPR035952; Rhomboid-like_sf.
DR   PANTHER; PTHR43731:SF31; PRESENILINS-ASSOCIATED RHOMBOID-LIKE PROTEIN, MITOCHONDRIAL; 1.
DR   PANTHER; PTHR43731; RHOMBOID PROTEASE; 1.
DR   Pfam; PF01694; Rhomboid; 1.
DR   SUPFAM; SSF144091; Rhomboid-like; 1.
DR   Genevisible; Q9H300; HS.
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="Presenilin-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"
FT   MUTAGEN         277
FT                   /note="S->A: Loss of cleavage of CLPB, DIABLO, STARD7 and
FT                   TTC19."
FT                   /evidence="ECO:0000269|PubMed:28288130"
FT   MUTAGEN         277
FT                   /note="S->G: Loss of PGAM5 cleavage."
FT                   /evidence="ECO:0000269|PubMed:22915595"
FT   MUTAGEN         335
FT                   /note="H->A: Loss of PGAM5 cleavage."
FT                   /evidence="ECO:0000269|PubMed:22915595"
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
//