PARL

Presenilins-associated rhomboid-like protein, mitochondrial (PSARL),[5] also known as PINK1/PGAM5-associated rhomboid-like protease (PARL),[6] is an inner mitochondrial membrane protein that in humans is encoded by the PARL gene on chromosome 3.[7] It is a member of the rhomboid family of intramembrane serine proteases.[8] This protein is involved in signal transduction and apoptosis, as well as neurodegenerative diseases and type 2 diabetes.[7][9]

See also: Prince Albert Radar Laboratory
PARL
Identifiers
AliasesPARL, PSARL, PSARL1, PSENIP2, RHBDS1, PRO2207, presenilin associated rhomboid like
External IDsOMIM: 607858 MGI: 1277152 HomoloGene: 10239 GeneCards: PARL
Orthologs
SpeciesHumanMouse
Entrez

55486

381038

Ensembl

ENSG00000175193

ENSMUSG00000033918

UniProt

Q9H300

Q5XJY4

RefSeq (mRNA)

NM_001005767

RefSeq (protein)

NP_001032728
NP_001311365
NP_001311366
NP_001311367
NP_061092

NP_001005767

Location (UCSC)Chr 3: 183.83 – 183.88 MbChr 16: 20.1 – 20.12 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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. [10]

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.[7]

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.[9]

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.[11] Variation in the sequence and/or expression of the gene encoding presenilins-associated rhomboid-like protein (PSARL) may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.[12] 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.[9]

Interactions

PARL has been shown to interact with:

References
  1. GRCh38: Ensembl release 89: ENSG00000175193 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000033918 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Q9H300 · PARL_HUMAN". UniProt. UniProt consortium. Retrieved 8 August 2023.
  6. Siebert V, Silber M, Heuten E, Muhle-Goll C, Lemberg MK (2022). "Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state". Journal of Biological Chemistry. 298 (9). doi:10.1016/j.jbc.2022.102321. PMC 9436811. PMID 35921890. 102321.
  7. "Entrez Gene: PARL presenilin associated, rhomboid-like".
  8. McQuibban GA, Saurya S, Freeman M (2003). "Mitochondrial membrane remodelling regulated by a conserved rhomboid protease". Nature. 423 (6939): 537–541. doi:10.1038/nature01633. PMID 12774122.
  9. Phasukkijwatana N, Kunhapan B, Stankovich J, Chuenkongkaew WL, Thomson R, Thornton T, Bahlo M, Mushiroda T, Nakamura Y, Mahasirimongkol S, Tun AW, Srisawat C, Limwongse C, Peerapittayamongkol C, Sura T, Suthammarak W, Lertrit P (Jul 2010). "Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand". Human Genetics. 128 (1): 39–49. doi:10.1007/s00439-010-0821-8. PMID 20407791. S2CID 394164.
  10. Pellegrini L, Scorrano L (Jul 2007). "A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis". Cell Death and Differentiation. 14 (7): 1275–84. doi:10.1038/sj.cdd.4402145. PMID 17464328.
  11. Heinitz S, Klein C, Djarmati A (Nov 2011). "The p.S77N presenilin-associated rhomboid-like protein mutation is not a frequent cause of early-onset Parkinson's disease". Movement Disorders. 26 (13): 2441–2. doi:10.1002/mds.23889. PMID 21953724. S2CID 45301679.
  12. Walder K, Kerr-Bayles L, Civitarese A, Jowett J, Curran J, Elliott K, Trevaskis J, Bishara N, Zimmet P, Mandarino L, Ravussin E, Blangero J, Kissebah A, Collier GR (Mar 2005). "The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes". Diabetologia. 48 (3): 459–68. doi:10.1007/s00125-005-1675-9. PMID 15729572.
  13. Shi G, Lee JR, Grimes DA, Racacho L, Ye D, Yang H, Ross OA, Farrer M, McQuibban GA, Bulman DE (May 2011). "Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease". Human Molecular Genetics. 20 (10): 1966–74. doi:10.1093/hmg/ddr077. PMID 21355049.

Further reading
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