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Protein

Presenilins-associated rhomboid-like protein, mitochondrial

Gene

PARL

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Required for the control of apoptosis during postnatal growth. Essential for proteolytic processing of an antiapoptotic form of OPA1 which prevents the release of mitochondrial cytochrome c in response to intrinsic apoptoptic signals (By similarity). Promotes changes in mitochondria morphology regulated by phosphorylation of P-beta domain.By similarity2 Publications

Catalytic activityi

Cleaves type-1 transmembrane domains using a catalytic dyad composed of serine and histidine that are contributed by different transmembrane domains.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei277 – 2771NucleophileBy similarity
Active sitei335 – 3351By similarity

GO - Molecular functioni

  • endopeptidase activity Source: ParkinsonsUK-UCL
  • serine-type endopeptidase activity Source: GO_Central

GO - Biological processi

  • membrane protein proteolysis Source: ParkinsonsUK-UCL
  • negative regulation of intrinsic apoptotic signaling pathway Source: Ensembl
  • negative regulation of release of cytochrome c from mitochondria Source: Ensembl
  • protein processing Source: GO_Central
  • proteolysis Source: ParkinsonsUK-UCL
  • regulation of protein targeting to mitochondrion Source: ParkinsonsUK-UCL
  • regulation of proteolysis Source: ParkinsonsUK-UCL
  • regulation of reactive oxygen species metabolic process Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Serine protease

Protein family/group databases

MEROPSiS54.009.

Names & Taxonomyi

Protein namesi
Recommended name:
Presenilins-associated rhomboid-like protein, mitochondrial (EC:3.4.21.105)
Alternative name(s):
Mitochondrial intramembrane cleaving protease PARL
Cleaved into the following chain:
P-beta
Short name:
Pbeta
Gene namesi
Name:PARL
Synonyms:PSARL
ORF Names:PRO2207
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:18253. PARL.

Subcellular locationi

Peptide P-beta :
  • Nucleus

  • Note: Translocated into the nucleus by an unknown mechanism.

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini53 – 10149Mitochondrial matrixSequence AnalysisAdd
BLAST
Transmembranei102 – 12120HelicalSequence AnalysisAdd
BLAST
Topological domaini122 – 16746Mitochondrial intermembraneSequence AnalysisAdd
BLAST
Transmembranei168 – 18720HelicalSequence AnalysisAdd
BLAST
Topological domaini188 – 20720Mitochondrial matrixSequence AnalysisAdd
BLAST
Transmembranei208 – 23023HelicalSequence AnalysisAdd
BLAST
Topological domaini231 – 24414Mitochondrial intermembraneSequence AnalysisAdd
BLAST
Transmembranei245 – 26218HelicalSequence AnalysisAdd
BLAST
Topological domaini263 – 27210Mitochondrial matrixSequence Analysis
Transmembranei273 – 28917HelicalSequence AnalysisAdd
BLAST
Topological domaini290 – 2956Mitochondrial intermembraneSequence Analysis
Transmembranei296 – 31823HelicalSequence AnalysisAdd
BLAST
Topological domaini319 – 33214Mitochondrial matrixSequence AnalysisAdd
BLAST
Transmembranei333 – 35422HelicalSequence AnalysisAdd
BLAST
Topological domaini355 – 37925Mitochondrial intermembraneSequence AnalysisAdd
BLAST

GO - Cellular componenti

  • integral component of membrane Source: UniProtKB-KW
  • mitochondrial inner membrane Source: ParkinsonsUK-UCL
  • mitochondrion Source: HPA
  • nucleus Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Membrane, Mitochondrion, Mitochondrion inner membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi65 – 651S → D: Strongly reduces the beta cleavage; when associated with D-69 and D-70. 1 Publication
Mutagenesisi69 – 691T → D: Strongly reduces the beta cleavage; when associated with D-65 and D-70. 1 Publication
Mutagenesisi70 – 701S → D: Strongly reduces the beta cleavage; when associated with D-65 and D-69. 1 Publication
Mutagenesisi76 – 761R → E: Abolishes the beta cleavage. 1 Publication
Mutagenesisi76 – 761R → G: Abolishes the beta cleavage. 1 Publication
Mutagenesisi77 – 771S → E: Abolishes the beta cleavage. 1 Publication
Mutagenesisi78 – 781A → E: Abolishes the beta cleavage. 1 Publication
Mutagenesisi79 – 791L → E: Abolishes the beta cleavage. 1 Publication

Organism-specific databases

PharmGKBiPA134939789.

Polymorphism and mutation databases

BioMutaiPARL.
DMDMi143811433.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transit peptidei1 – 5252Mitochondrion1 PublicationAdd
BLAST
Chaini53 – 379327Presenilins-associated rhomboid-like protein, mitochondrialPRO_0000027386Add
BLAST
Peptidei53 – 7725P-beta1 PublicationPRO_0000027387Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei65 – 651Phosphoserine1 Publication
Modified residuei69 – 691Phosphothreonine1 Publication
Modified residuei70 – 701Phosphoserine1 Publication

Post-translational modificationi

P-beta is proteolytically processed (beta-cleavage) in a PARL-dependent manner. The cleavage is inhibited when residues Ser-65, Thr-69 and Ser-70 are all phosphorylated.1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiQ9H300.
PaxDbiQ9H300.
PRIDEiQ9H300.

PTM databases

PhosphoSiteiQ9H300.

Miscellaneous databases

PMAP-CutDBQ9H300.

Expressioni

Gene expression databases

BgeeiQ9H300.
CleanExiHS_PARL.
ExpressionAtlasiQ9H300. baseline and differential.
GenevestigatoriQ9H300.

Organism-specific databases

HPAiHPA019545.

Interactioni

Subunit structurei

Interacts with PSEN1 and PSEN2. Binds OPA1.1 Publication

Protein-protein interaction databases

BioGridi120678. 7 interactions.
STRINGi9606.ENSP00000325421.

Structurei

3D structure databases

ProteinModelPortaliQ9H300.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the peptidase S54 family.Curated

Keywords - Domaini

Transit peptide, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0705.
GeneTreeiENSGT00390000013063.
HOGENOMiHOG000230670.
HOVERGENiHBG082107.
InParanoidiQ9H300.
KOiK09650.
OMAiHEMRTNS.
OrthoDBiEOG7NGQBT.
PhylomeDBiQ9H300.
TreeFamiTF313603.

Family and domain databases

Gene3Di1.20.1540.10. 1 hit.
InterProiIPR002610. Peptidase_S54_rhomboid.
IPR022764. Peptidase_S54_rhomboid_dom.
[Graphical view]
PANTHERiPTHR22936. PTHR22936. 1 hit.
PfamiPF01694. Rhomboid. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9H300-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAWRGWAQRG WGCGQAWGAS VGGRSCEELT AVLTPPQLLG RRFNFFIQQK
60 70 80 90 100
CGFRKAPRKV EPRRSDPGTS GEAYKRSALI PPVEETVFYP SPYPIRSLIK
110 120 130 140 150
PLFFTVGFTG CAFGSAAIWQ YESLKSRVQS YFDGIKADWL DSIRPQKEGD
160 170 180 190 200
FRKEINKWWN NLSDGQRTVT GIIAANVLVF CLWRVPSLQR TMIRYFTSNP
210 220 230 240 250
ASKVLCSPML LSTFSHFSLF HMAANMYVLW SFSSSIVNIL GQEQFMAVYL
260 270 280 290 300
SAGVISNFVS YVGKVATGRY GPSLGASGAI MTVLAAVCTK IPEGRLAIIF
310 320 330 340 350
LPMFTFTAGN ALKAIIAMDT AGMILGWKFF DHAAHLGGAL FGIWYVTYGH
360 370
ELIWKNREPL VKIWHEIRTN GPKKGGGSK
Length:379
Mass (Da):42,190
Last modified:April 3, 2007 - v2
Checksum:i2B07EF04C7130B0B
GO
Isoform 2 (identifier: Q9H300-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     203-253: KVLCSPMLLSTFSHFSLFHMAANMYVLWSFSSSIVNILGQEQFMAVYLSAG → S

Show »
Length:329
Mass (Da):36,589
Checksum:i55E752160C632DBF
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti137 – 1371A → G.
Corresponds to variant rs4912470 [ dbSNP | Ensembl ].
VAR_029801
Natural varianti262 – 2621V → L.2 Publications
Corresponds to variant rs3732581 [ dbSNP | Ensembl ].
VAR_021578

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei203 – 25351KVLCS…YLSAG → S in isoform 2. 1 PublicationVSP_013310Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF197937 mRNA. Translation: AAG28519.1.
BC003653 mRNA. Translation: AAH03653.1.
BC014058 mRNA. Translation: AAH14058.1.
AF116692 mRNA. Translation: AAF71112.1.
CCDSiCCDS3248.1. [Q9H300-1]
CCDS33897.1. [Q9H300-2]
RefSeqiNP_001032728.1. NM_001037639.1. [Q9H300-2]
NP_061092.3. NM_018622.5. [Q9H300-1]
UniGeneiHs.478469.

Genome annotation databases

EnsembliENST00000311101; ENSP00000310676; ENSG00000175193. [Q9H300-2]
ENST00000317096; ENSP00000325421; ENSG00000175193. [Q9H300-1]
GeneIDi55486.
KEGGihsa:55486.
UCSCiuc003fmd.3. human. [Q9H300-1]
uc003fme.3. human. [Q9H300-2]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF197937 mRNA. Translation: AAG28519.1.
BC003653 mRNA. Translation: AAH03653.1.
BC014058 mRNA. Translation: AAH14058.1.
AF116692 mRNA. Translation: AAF71112.1.
CCDSiCCDS3248.1. [Q9H300-1]
CCDS33897.1. [Q9H300-2]
RefSeqiNP_001032728.1. NM_001037639.1. [Q9H300-2]
NP_061092.3. NM_018622.5. [Q9H300-1]
UniGeneiHs.478469.

3D structure databases

ProteinModelPortaliQ9H300.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi120678. 7 interactions.
STRINGi9606.ENSP00000325421.

Protein family/group databases

MEROPSiS54.009.

PTM databases

PhosphoSiteiQ9H300.

Polymorphism and mutation databases

BioMutaiPARL.
DMDMi143811433.

Proteomic databases

MaxQBiQ9H300.
PaxDbiQ9H300.
PRIDEiQ9H300.

Protocols and materials databases

DNASUi55486.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000311101; ENSP00000310676; ENSG00000175193. [Q9H300-2]
ENST00000317096; ENSP00000325421; ENSG00000175193. [Q9H300-1]
GeneIDi55486.
KEGGihsa:55486.
UCSCiuc003fmd.3. human. [Q9H300-1]
uc003fme.3. human. [Q9H300-2]

Organism-specific databases

CTDi55486.
GeneCardsiGC03M183547.
HGNCiHGNC:18253. PARL.
HPAiHPA019545.
MIMi607858. gene.
neXtProtiNX_Q9H300.
PharmGKBiPA134939789.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiCOG0705.
GeneTreeiENSGT00390000013063.
HOGENOMiHOG000230670.
HOVERGENiHBG082107.
InParanoidiQ9H300.
KOiK09650.
OMAiHEMRTNS.
OrthoDBiEOG7NGQBT.
PhylomeDBiQ9H300.
TreeFamiTF313603.

Miscellaneous databases

ChiTaRSiPARL. human.
GeneWikiiPARL.
GenomeRNAii55486.
NextBioi59867.
PMAP-CutDBQ9H300.
PROiQ9H300.
SOURCEiSearch...

Gene expression databases

BgeeiQ9H300.
CleanExiHS_PARL.
ExpressionAtlasiQ9H300. baseline and differential.
GenevestigatoriQ9H300.

Family and domain databases

Gene3Di1.20.1540.10. 1 hit.
InterProiIPR002610. Peptidase_S54_rhomboid.
IPR022764. Peptidase_S54_rhomboid_dom.
[Graphical view]
PANTHERiPTHR22936. PTHR22936. 1 hit.
PfamiPF01694. Rhomboid. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of presenilin-1 and -2."
    Pellegrini L., Passer B.J., Canelles M., Lefterov I., Ganjei J.K., Fowlkes B.J., Koonin E.V., D'Adamio L.
    J. Alzheimers Dis. 3:181-190(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT LEU-262, INTERACTION WITH PSEN1 AND PSEN2.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
    Tissue: Lung.
  3. "Functional prediction of the coding sequences of 121 new genes deduced by analysis of cDNA clones from human fetal liver."
    Zhang C., Yu Y., Zhang S., Wei H., Zhou G., Ouyang S., Luo L., Bi J., Liu M., He F.
    Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 192-379 (ISOFORM 1), VARIANT LEU-262.
    Tissue: Fetal liver.
  4. "Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields Pbeta, a nuclear-targeted peptide."
    Sik A., Passer B.J., Koonin E.V., Pellegrini L.
    J. Biol. Chem. 279:15323-15329(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 53-61 AND 78-85, FUNCTION IN BETA CLEAVAGE, MUTAGENESIS OF ARG-76; SER-77; ALA-78 AND LEU-79.
  5. "Phosphorylation and cleavage of presenilin-associated rhomboid-like protein (PARL) promotes changes in mitochondrial morphology."
    Jeyaraju D.V., Xu L., Letellier M.-C., Bandaru S., Zunino R., Berg E.A., McBride H.M., Pellegrini L.
    Proc. Natl. Acad. Sci. U.S.A. 103:18562-18567(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, PHOSPHORYLATION AT SER-65; THR-69 AND SER-70 OF P-BETA, MUTAGENESIS OF SER-65; THR-69 AND SER-70, SUBCELLULAR LOCATION, TOPOLOGY, BETA-CLEAVAGE.

Entry informationi

Entry nameiPARL_HUMAN
AccessioniPrimary (citable) accession number: Q9H300
Secondary accession number(s): Q96CQ4, Q9BTJ6, Q9P1E3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 12, 2005
Last sequence update: April 3, 2007
Last modified: May 27, 2015
This is version 120 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Peptidase families
    Classification of peptidase families and list of entries
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.