PARL Protease: A Glimpse at Intramembrane Proteolysis in the Inner Mitochondrial Membrane

• Published in: Journal of molecular biology Vol. 432; no. 18; pp. 5052 - 5062
• Main Authors: Lysyk, Laine, Brassard, Raelynn, Touret, Nicolas, Lemieux, M. Joanne
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 21.08.2020
• Subjects: Gene Expression Regulation; Homeostasis; Humans; intramembrane protease; Metalloproteases - chemistry; Metalloproteases - metabolism; mitochondria; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - metabolism; Parkinson Disease - metabolism; PARL; PINK1; Protein Conformation; Proteolysis; rhomboid protease; rhomboid protease; KO; mitochondria; IMM; MTS; PARL; S2P; PINK1; SPP; PD; intramembrane protease; TM; PGAM5; HEXXH
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2020.04.006

Intramembrane proteolysis, although once a controversial concept, is a widely studied field. Four classes of intramembrane proteases have been identified and are classified by their catalytic mechanism of peptide bond hydrolysis: metallo, glutamyl, aspartyl, and serine proteases. One of the most studied of these classes is the rhomboid superfamily of serine intramembrane proteases. Rhomboids consist of six or seven transmembrane segments that form a helical bundle within the membrane and are involved in a multitude of cellular processes. These proteases are characterized by a catalytic dyad composed of a serine and a histidine residue, which distinguishes them from classical serine proteases wherein a catalytic triad is utilized. Of all currently identified rhomboid proteases, one that is of great interest is the mammalian mitochondrial rhomboid protease PARL. Most well known for its processing of the kinase PINK1 and potential link to Parkinson's disease, PARL has been shown to cleave a variety of substrates within the cell including PGAM5, Smac, TTC19, and others. While recent proteomic studies have provided insight on new potential substrates of PARL, its regulation, activity, and role in maintaining mitochondrial homeostasis remain largely unknown. [Display omitted] •Four classes of intramembrane proteases have been identified: serine, aspartyl, glutamyl, and metalloproteases.•Rhomboid proteases are ubiquitously expressed serine intramembrane proteases with many cellular roles.•PARL is a rhomboid intramembrane protease found in the inner mitochondrial membrane of mammalian cells.•PARL is proposed to cleave numerous substrates; however, its physiological role and regulation remain unclear.