PITRM1
Description
The PITRM1 (pitrilysin metallopeptidase 1) is a protein-coding gene located on chromosome 10.
Pitrilysin metallopeptidase 1, also known as presequence protease, mitochondrial (PreP) and metalloprotease 1 (MTP-1), is an enzyme encoded by the PITRM1 gene in humans. It is sometimes called metalloprotease 1 (MP1). PreP contributes to proteostasis by utilizing a large catalytic chamber to degrade toxic peptides, including mitochondrial presequences and β-amyloid. PreP deficiency is associated with Alzheimer's disease. Reduced PreP levels through RNAi knockdown have been linked to impaired maturation of the protein Frataxin. The PITRM1 gene is located on chromosome 10q15.2 and comprises 28 exons. PreP is a 117 kDa M16C enzyme widely expressed in human tissues. It consists of PreP-N and PreP-C domains connected by an extended helical hairpin. Its structure suggests that substrate selection by size-exclusion is a conserved mechanism in M16C proteases. PreP is a Zn2+-dependent and ATP-independent metalloprotease that does not select substrates based on post-translational modifications or degradation tags. It employs a negatively charged catalytic chamber to engulf substrate peptides up to ~65 residues while excluding larger, folded proteins.
PITRM1 is a metalloendopeptidase located in the mitochondrial matrix that primarily functions in the cleavage and degradation of peptides, rather than protein processing. It exhibits ATP-independent activity, specifically targeting peptides in the range of 5 to 65 residues. PITRM1 shows a preference for cleaving after small polar residues and before basic residues, but its cleavage position isn't fixed. It degrades the transit peptides of mitochondrial proteins after their cleavage and also degrades other unstructured peptides. It can degrade amyloid-beta protein 40, a product of APP processing, when it accumulates in the mitochondria. PITRM1 is a highly efficient protease, especially towards amyloid-beta protein 40, cleaving it at a specific site and releasing digested peptide intermediates that can be further cleaved. PITRM1 can also degrade amyloid-beta protein 42.
PITRM1 is also known as MP1, PreP, SCAR30.
