PARL

PARL
Identifiers
Aliases	PARL, PSARL, PSARL1, PSENIP2, RHBDS1, PRO2207, presenilin associated rhomboid like
External IDs	MGI: 1277152 HomoloGene: 10239 GeneCards: PARL
Gene ontology Molecular function • peptidase activity • serine-type peptidase activity • endopeptidase activity • serine-type endopeptidase activity • protein binding • hydrolase activity Cellular component • integral component of membrane • mitochondrial inner membrane • membrane • mitochondrion • nucleus Biological process • negative regulation of release of cytochrome c from mitochondria • protein processing • regulation of mitophagy • regulation of reactive oxygen species metabolic process • regulation of protein targeting to mitochondrion • regulation of proteolysis • proteolysis • membrane protein proteolysis • negative regulation of intrinsic apoptotic signaling pathway Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	55486	381038
Ensembl	ENSG00000175193	ENSMUSG00000033918
UniProt	Q9H300	Q5XJY4
RefSeq (mRNA)	NM_001037639 NM_001037640 NM_018622 NM_001324436 NM_001324437 NM_001324438	NM_001005767
RefSeq (protein)	NP_001032728.1 NP_061092.3	NP_001005767.1
Location (UCSC)	Chr 3: 183.83 – 183.88 Mb	Chr 16: 20.28 – 20.3 Mb
PubMed search	[1]	[2]
Wikidata

Presenilins-associated rhomboid-like protein, mitochondrial also known as mitochondrial intramembrane cleaving protease PARL is an inner mitochondrial membrane protein that in humans is encoded by the PARL gene on chromosome 3.^[3] It is a member of the rhomboid family of intramembrane serine proteases.^[4] This protein is involved in signal transduction and apoptosis, as well as neurodegenerative diseases and type 2 diabetes.^[3][5]

Structure

Rhomboid family members share a conserved core of six transmembrane helices (TMHs), with the Ser and His residues required to form the catalytic dyad embedded in TMH-4 and TMH-6, respectively. This dyad is found deep below the membrane surface, which indicates that the hydrolysis of peptide bonds occurs within the hydrophobic phospholipid bilayer membrane. As a member of the Parl subfamily, PARL has an additional N-terminal TMH which may form a loop to the catalytic core. ^[6]

Function

This gene encodes a mitochondrial integral membrane protein. Following proteolytic processing of this protein, a small peptide (P-beta) is formed and translocated to the nucleus. This gene may be involved in signal transduction via regulated intramembrane proteolysis of membrane-tethered precursor proteins. Variation in this gene has been associated with increased risk for type 2 diabetes. Alternative splicing results in multiple transcript variants encoding different isoforms.^[3]

Additionally, PARL is involved in apoptosis through its interactions with the mitochondrial GTPase optic atrophy 1 (OPA1) and the Bcl-2 family-related protein HAX1. OPA1 mainly regulates mitochondrial fusion in the mitochondrial inner membrane, but after proteolytic cleavage by PARL, its short, soluble form contributes to inhibiting apoptosis by slowing down cytochrome c release, and thus, proapoptotic signaling. Alternatively, PARL can inhibit apoptosis by coordinating with HAX1 to activate HtrA2 protease, thus preventing the accumulation of the proapoptotic Bax.^[5]

Clinical significance

It has been shown that the p.S77N presenilin-associated rhomboid-like protein mutation is not a frequent cause of early-onset Parkinson’s disease.^[7] Variation in presenilins-associated rhomboid-like protein (PSARL) sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.^[8] Mutations in PARL may also be involved in Leber hereditary optic neuropathy by disrupting normal function of the mitochondria, thus promoting retinal ganglion cell death and neurodegeneration.^[5]

Interactions

PARL has been shown to interact with:

• PINK1,^[9]
• OPA1,^[5] and
• HAX1.^[5]

References

Further reading