Biology:PARL
 Generic protein structure example |
Presenilins-associated rhomboid-like protein, mitochondrial (PSARL),[1] also known as PINK1/PGAM5-associated rhomboid-like protease (PARL),[2] 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 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.[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:
References
- ↑ "Q9H300 · PARL_HUMAN". UniProt consortium. https://www.uniprot.org/uniprotkb/Q9H300/entry.
- ↑ "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). 2022. doi:10.1016/j.jbc.2022.102321. 102321. PMID 35921890.
- ↑ 3.0 3.1 3.2 "Entrez Gene: PARL presenilin associated, rhomboid-like". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55486.
- ↑ "Mitochondrial membrane remodelling regulated by a conserved rhomboid protease". Nature 423 (6939): 537–541. 2003. doi:10.1038/nature01633. PMID 12774122. Bibcode: 2003Natur.423..537M.
- ↑ 5.0 5.1 5.2 5.3 5.4 "Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand". Human Genetics 128 (1): 39–49. Jul 2010. doi:10.1007/s00439-010-0821-8. PMID 20407791.
- ↑ "A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis". Cell Death and Differentiation 14 (7): 1275–84. Jul 2007. doi:10.1038/sj.cdd.4402145. PMID 17464328.
- ↑ "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. Nov 2011. doi:10.1002/mds.23889. PMID 21953724.
- ↑ "The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes". Diabetologia 48 (3): 459–68. Mar 2005. doi:10.1007/s00125-005-1675-9. PMID 15729572.
- ↑ "Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease". Human Molecular Genetics 20 (10): 1966–74. May 2011. doi:10.1093/hmg/ddr077. PMID 21355049.
Further reading
- "Phosphorylation and cleavage of presenilin-associated rhomboid-like protein (PARL) promotes changes in mitochondrial morphology". Proceedings of the National Academy of Sciences of the United States of America 103 (49): 18562–7. Dec 2006. doi:10.1073/pnas.0604983103. PMID 17116872. Bibcode: 2006PNAS..10318562J.
- "PARL Leu262Val is not associated with fasting insulin levels in UK populations". Diabetologia 49 (11): 2649–52. Nov 2006. doi:10.1007/s00125-006-0443-9. PMID 17019603.
- "The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes". Diabetologia 48 (3): 459–68. Mar 2005. doi:10.1007/s00125-005-1675-9. PMID 15729572.
- "Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields Pbeta, a nuclear-targeted peptide". The Journal of Biological Chemistry 279 (15): 15323–9. Apr 2004. doi:10.1074/jbc.M313756200. PMID 14732705.
- "Mitochondrial membrane remodelling regulated by a conserved rhomboid protease". Nature 423 (6939): 537–41. May 2003. doi:10.1038/nature01633. PMID 12774122. Bibcode: 2003Natur.423..537M.
- "PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of Presenilin-1 and -2". Journal of Alzheimer's Disease 3 (2): 181–190. Apr 2001. doi:10.3233/jad-2001-3203. PMID 12214059.
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