# PARL

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{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{See also|Prince Albert Radar Laboratory}}
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'''Presenilins-associated rhomboid-like protein, mitochondrial''' (PSARL),<ref>{{cite web|url=https://www.uniprot.org/uniprotkb/Q9H300/entry|title=Q9H300 · PARL_HUMAN|website=UniProt|publisher=UniProt consortium|access-date=8 August 2023}}</ref> also known as '''PINK1/PGAM5-associated rhomboid-like protease''' (PARL),<ref>{{cite journal|vauthors=Siebert V, Silber M, Heuten E, Muhle-Goll C, Lemberg MK|title=Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state|journal=Journal of Biological Chemistry|volume=298|issue=9|id=102321|pmid=35921890|doi=10.1016/j.jbc.2022.102321|year=2022|doi-access=free |pmc=9436811}}</ref> is an [inner mitochondrial membrane](/source/inner_mitochondrial_membrane) [protein](/source/protein) that in humans is encoded by the ''PARL'' [gene](/source/gene) on chromosome 3.<ref name="entrez">{{cite web | title = Entrez Gene: PARL presenilin associated, rhomboid-like| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=55486| access-date = }}</ref> It is a member of the [rhomboid](/source/Rhomboid_protease) family of intramembrane [serine protease](/source/serine_protease)s.<ref>{{cite journal|vauthors=McQuibban GA, Saurya S, Freeman M|title=Mitochondrial membrane remodelling regulated by a conserved rhomboid protease|journal=Nature|volume=423|pages=537–541|year=2003|doi=10.1038/nature01633|pmid=12774122|issue=6939|doi-access=free|bibcode=2003Natur.423..537M }}</ref> This protein is involved in [signal transduction](/source/signal_transduction) and [apoptosis](/source/apoptosis), as well as [neurodegenerative disease](/source/neurodegenerative_disease)s and [type 2 diabetes](/source/type_2_diabetes).<ref name="entrez"/><ref name=pmid20407791>{{cite journal | vauthors = 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 | title = Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand | journal = Human Genetics | volume = 128 | issue = 1 | pages = 39–49 | date = Jul 2010 | pmid = 20407791 | doi = 10.1007/s00439-010-0821-8 | s2cid = 394164 }}</ref>

==Structure==

Rhomboid family members share a conserved core of six [transmembrane](/source/transmembrane) helices (TMHs), with the Ser and His residues required to form the [catalytic](/source/catalytic) [dyad](/source/dyad_(biology)) 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](/source/hydrophobic) [phospholipid bilayer](/source/phospholipid_bilayer) membrane. As a member of the Parl subfamily, PARL has an additional [N-terminal](/source/N-terminal) TMH which may form a loop to the catalytic core. 
<ref>{{cite journal | vauthors = Pellegrini L, Scorrano L | title = A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis | journal = Cell Death and Differentiation | volume = 14 | issue = 7 | pages = 1275–84 | date = Jul 2007 | pmid = 17464328 | doi = 10.1038/sj.cdd.4402145 | doi-access = free }}</ref>

== Function ==

This gene encodes a mitochondrial [integral membrane protein](/source/integral_membrane_protein). Following [proteolytic](/source/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](/source/type_2_diabetes). Alternative splicing results in multiple transcript variants encoding different isoforms.<ref name="entrez"/>

Additionally, PARL is involved in apoptosis through its interactions with the mitochondrial [GTPase](/source/GTPase) optic atrophy 1 ([OPA1](/source/OPA1)) and the [Bcl-2 family](/source/Bcl-2_family)-related protein [HAX1](/source/HAX1). OPA1 mainly regulates [mitochondrial fusion](/source/mitochondrial_fusion) in the [mitochondrial inner membrane](/source/mitochondrial_inner_membrane), but after [proteolytic cleavage](/source/proteolysis) by PARL, its short, soluble form contributes to inhibiting apoptosis by slowing down [cytochrome c](/source/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](/source/Bcl-2-associated_X_protein).<ref name=pmid20407791/>

== 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](/source/Parkinson's_disease).<ref>{{cite journal | vauthors = Heinitz S, Klein C, Djarmati A | title = The p.S77N presenilin-associated rhomboid-like protein mutation is not a frequent cause of early-onset Parkinson's disease | journal = [Movement Disorders](/source/Movement_Disorders_(journal)) | volume = 26 | issue = 13 | pages = 2441–2 | date = Nov 2011 | pmid = 21953724 | doi = 10.1002/mds.23889 | s2cid = 45301679 }}</ref> 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](/source/metabolic_syndrome).<ref>{{cite journal | vauthors = 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 | title = The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes | journal = [Diabetologia](/source/Diabetologia) | volume = 48 | issue = 3 | pages = 459–68 | date = Mar 2005 | pmid = 15729572 | doi = 10.1007/s00125-005-1675-9 | doi-access = free | hdl = 10536/DRO/DU:30003156 | hdl-access = free }}</ref> Mutations in ''PARL'' may also be involved in [Leber hereditary optic neuropathy](/source/Leber_hereditary_optic_neuropathy) by disrupting normal function of the [mitochondria](/source/mitochondria), thus promoting [retinal ganglion cell](/source/retinal_ganglion_cell) death and neurodegeneration.<ref name=pmid20407791/>

== Interactions  ==

PARL has been shown to interact with:
* [PINK1](/source/PINK1),<ref>{{cite journal | vauthors = Shi G, Lee JR, Grimes DA, Racacho L, Ye D, Yang H, Ross OA, Farrer M, McQuibban GA, Bulman DE | title = Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease | journal = Human Molecular Genetics | volume = 20 | issue = 10 | pages = 1966–74 | date = May 2011 | pmid = 21355049 | doi = 10.1093/hmg/ddr077 | doi-access =  }}</ref>
* [OPA1](/source/OPA1),<ref name=pmid20407791/> and
* [HAX1](/source/HAX1).<ref name=pmid20407791/>

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Jeyaraju DV, Xu L, Letellier MC, Bandaru S, Zunino R, Berg EA, McBride HM, Pellegrini L | title = Phosphorylation and cleavage of presenilin-associated rhomboid-like protein (PARL) promotes changes in mitochondrial morphology | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 49 | pages = 18562–7 | date = Dec 2006 | pmid = 17116872 | pmc = 1693702 | doi = 10.1073/pnas.0604983103 | bibcode = 2006PNAS..10318562J | doi-access = free }}
* {{cite journal | vauthors = Fawcett KA, Wareham NJ, Luan J, Syddall H, Cooper C, O'Rahilly S, Day IN, Sandhu MS, Barroso I | title = PARL Leu262Val is not associated with fasting insulin levels in UK populations | journal = Diabetologia | volume = 49 | issue = 11 | pages = 2649–52 | date = Nov 2006 | pmid = 17019603 | pmc = 2672784 | doi = 10.1007/s00125-006-0443-9 }}
* {{cite journal | vauthors = 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 | title = The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes | journal = Diabetologia | volume = 48 | issue = 3 | pages = 459–68 | date = Mar 2005 | pmid = 15729572 | doi = 10.1007/s00125-005-1675-9 | doi-access = free | hdl = 10536/DRO/DU:30003156 | hdl-access = free }}
* {{cite journal | vauthors = Sík A, Passer BJ, Koonin EV, Pellegrini L | title = Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields Pbeta, a nuclear-targeted peptide | journal = The Journal of Biological Chemistry | volume = 279 | issue = 15 | pages = 15323–9 | date = Apr 2004 | pmid = 14732705 | doi = 10.1074/jbc.M313756200 | doi-access = free }}
* {{cite journal | vauthors = McQuibban GA, Saurya S, Freeman M | title = Mitochondrial membrane remodelling regulated by a conserved rhomboid protease | journal = Nature | volume = 423 | issue = 6939 | pages = 537–41 | date = May 2003 | pmid = 12774122 | doi = 10.1038/nature01633 | bibcode = 2003Natur.423..537M | s2cid = 4398146 | doi-access = free }}
* {{cite journal | vauthors = Pellegrini L, Passer BJ, Canelles M, Lefterov I, Ganjei JK, Fowlkes BJ, Koonin EV, D'Adamio L | title = PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of Presenilin-1 and -2 | journal = Journal of Alzheimer's Disease | volume = 3 | issue = 2 | pages = 181–190 | date = Apr 2001 | pmid = 12214059 | doi =  10.3233/jad-2001-3203}}

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Category:Proteins

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Adapted from the Wikipedia article [PARL](https://en.wikipedia.org/wiki/PARL) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/PARL?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.