PITRM1

Pitrilysin metallopeptidase 1 also known as presequence protease, mitochondrial (PreP) and metalloprotease 1 (MTP-1) is an enzyme that in humans is encoded by the PITRM1 gene.^[5][6][7] It is also sometimes called metalloprotease 1 (MP1).PreP facilitates proteostasis by utilizing an ~13300-A(3) catalytic chamber to degrade toxic peptides, including mitochondrial presequences and β-amyloid.^[8] Deficiency of PreP is found associated with Alzheimer's disease. Reduced levels of PreP via RNAi mediated knockdown have been shown to lead to defective maturation of the protein Frataxin.^[9]

PITRM1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4L3T, 4NGE, 4RPU
Identifiers
Aliases	PITRM1, MP1, PreP, pitrilysin metallopeptidase 1, SCAR30
External IDs	OMIM: 618211; MGI: 1916867; HomoloGene: 5742; GeneCards: PITRM1; OMA:PITRM1 - orthologs
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10p15.2 Start 3,137,728 bp[1] End 3,172,841 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13|13 A1 Start 6,598,185 bp[2] End 6,630,551 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in apex of heart right adrenal cortex anterior pituitary left testis left adrenal gland left adrenal cortex right frontal lobe Descending thoracic aorta right testis left ovary Top expressed in tail of embryo genital tubercle fetal liver hematopoietic progenitor cell gastrula epiblast primitive streak placenta cumulus cell hair follicle endothelial cell of lymphatic vessel More reference expression data BioGPS More reference expression data
Gene ontology Molecular function peptidase activity enzyme activator activity catalytic activity hydrolase activity metal ion binding metallopeptidase activity metalloendopeptidase activity zinc ion binding Cellular component mitochondrion mitochondrial matrix Biological process positive regulation of catalytic activity protein targeting to mitochondrion proteolysis protein processing Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10531 69617 Ensembl ENSG00000107959 ENSMUSG00000021193 UniProt Q5JRX3 Q8K411 RefSeq (mRNA) NM_001242307 NM_001242309 NM_014889 NM_014968 NM_001347725 NM_001347726 NM_001347727 NM_001347728 NM_001347729 NM_001347730 NM_145131 NM_001360106 RefSeq (protein) NP_001229236 NP_001229238 NP_001334654 NP_001334655 NP_001334656 NP_001334657 NP_001334658 NP_001334659 NP_055704 NP_660113 NP_001347035 Location (UCSC) Chr 10: 3.14 – 3.17 Mb Chr 13: 6.6 – 6.63 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Gene

The PITRM1 gene is located at chromosome 10q15.2, consisting of 28 exons.

Protein

PreP is a 117 kDa M16C enzyme that is widely expressed in human tissues.^[10] PreP is composed of PreP-N (aa 33-509) and PreP-C (aa 576-1037) domains, which are connected by an extended helical hairpin (aa 510-575). Its structure demonstrates that substrate selection by size-exclusion is a conserved mechanism in M16C proteases.^[8]

Function

PreP is an Zn²⁺-dependent and ATP-independent metalloprotease, it does not select substrates on the basis of post-translational modifications or embedded degradation tags.^[11][12][13] Instead, it uses a negatively charged catalytic chamber to engulf substrates peptides of up to ~65 residues while excluding larger, folded proteins.^[14][15] It primarily localizes to the mitochondrial matrix, and cuts a range of peptides into recyclable fragments.^[16][17] The substrates of PreP are vital to proteostasis, as they can insert to mitochondrial membranes, disrupting electrical potential and uncoupling respiration.^[18][19] Thus deletion of PRTRM1 leads to a delayed growth phenotype.^[20][21] Notabley, PreP degrades several functionally relevant Aβ species, the aggregates of which are toxic to the neuron and play a key role in AD pathogenesis.^[22][14][23]

Clinical significance

PreP is the Aβ-degrading protease in mitochondria. Immune-depletion of PreP in brain mitochondria prevents degradation of mitochondrial Aβ, and PreP activity is found diminished in AD patients.^[8] It has been reported that the loss of PreP activity is due to methionine oxidation and this study provides a rational basis for therapeutic intervention in conditions characterized by excessive oxidation of PreP.^[24] A recent study also suggests that PreP regulates islet amyloid polypeptide in beta cells.^[25] Two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) were reported to be associated with an autosomal recessive, slowly progressive syndrome. Clinical features include mental retardation, spinocerebellar ataxia, cognitive decline and psychosis.^[26] A mouse model hemizygous for PITRM1 displayed progressive ataxia which was suggested to be linked to brain degenerative lesions, including accumulation of Aβ‐positive amyloid deposits. Recently, two brothers from a consanguineous family presenting with childhood-onset recessive cerebellar pathology were shown to carry a homozygous mutation in PITRM1 (c.2795C>T, p.T931M). This mutation resulted in 95% reduction in PITRM1 protein.^[27] PITRM1 knockdown was shown to lead to reduced levels of mature Frataxin protein,^[28] a protein that when deficient causes Friedreich's ataxia, and may be implicated in pathology in patients carrying PITRM1 mutations.

Interactions

PITRM1 has been shown to interact with the following proteins: CCL22, CGB2, DDX41, DEFB104A, HDHD3, MRPL12, NDUFV2, PRDX6, PRKCSH, RARS2, RIF1, SUCLG2, TEKT3, TERF2, and VAPB.^[29]