PARL

Description

The PARL (presenilin associated rhomboid like) is a protein-coding gene located on chromosome 3.

PARL, short for Presenilin-associated rhomboid-like protein, mitochondrial, is an inner mitochondrial membrane protein encoded by the PARL gene on chromosome 3 in humans. It belongs to the rhomboid family of intramembrane serine proteases. This protein plays a key role in signal transduction, apoptosis, and is implicated in neurodegenerative diseases and type 2 diabetes. PARL has a conserved core structure, with six transmembrane helices (TMHs), featuring a catalytic dyad composed of Ser and His residues within TMH-4 and TMH-6, respectively. This dyad is situated deep within the hydrophobic phospholipid bilayer membrane, suggesting that peptide bond hydrolysis occurs within the membrane. As a member of the Parl subfamily, PARL possesses an additional N-terminal TMH, which may form a loop connecting to the catalytic core. The PARL gene encodes a mitochondrial integral membrane protein. Following proteolytic processing, a small peptide called P-beta is generated and transported to the nucleus. Variations in the PARL gene have been linked to an increased risk of type 2 diabetes.

PARL is essential for controlling apoptosis during postnatal growth. It is crucial for proteolytic processing of an antiapoptotic form of OPA1, preventing the release of mitochondrial cytochrome c in response to intrinsic apoptotic signals. PARL also facilitates the maturation of PINK1 into its active 52kDa form, following cleavage by mitochondrial-processing peptidase (MPP). In damaged mitochondria, PARL promotes the cleavage of serine/threonine-protein phosphatase PGAM5 in response to loss of mitochondrial membrane potential. Importantly, PARL can differentially cleave PINK1 and PGAM5 based on the mitochondrial health status, dissociating from PINK1 and associating with PGAM5 when mitochondrial membrane potential is lost. Furthermore, PARL is involved in processing CLPB into a form with enhanced protein disaggregase activity by removing an autoinhibitory N-terminal peptide, leading to the promotion of DIABLO/SMAC processing within the mitochondrion, which is necessary for DIABLO's apoptotic activity. PARL is also required for the cleavage of STARD7 and TTC19. Additionally, PARL contributes to changes in mitochondria morphology, regulated by the phosphorylation of its P-beta domain.

PARL is also known as PRO2207, PSARL, PSARL1, PSENIP2, RHBDS1.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing