PITRM1

PITRM1 is an ATP-dependent metalloprotease that degrades post-cleavage mitochondrial transit peptides. The encoded protein binds zinc and can also degrade amyloid beta A4 protein, suggesting a possible role in Alzheimer's disease.

Full Name

pitrilysin metallopeptidase 1

Function

Metalloendopeptidase of the mitochondrial matrix that functions in peptide cleavage and degradation rather than in protein processing (PubMed:10360838, PubMed:16849325, PubMed:19196155, PubMed:24931469).
Has an ATP-independent activity (PubMed:16849325).
Specifically cleaves peptides in the range of 5 to 65 residues (PubMed:19196155).
Shows a preference for cleavage after small polar residues and before basic residues, but without any positional preference (PubMed:10360838, PubMed:19196155, PubMed:24931469).
Degrades the transit peptides of mitochondrial proteins after their cleavage (PubMed:19196155).
Also degrades other unstructured peptides (PubMed:19196155).
It is also able to degrade amyloid-beta protein 40, one of the peptides produced by APP processing, when it accumulates in mitochondrion (PubMed:16849325, PubMed:24931469, PubMed:26697887).
It is a highly efficient protease, at least toward amyloid-beta protein 40 (PubMed:24931469, PubMed:29764912, PubMed:29383861).
Cleaves that peptide at a specific position and is probably not processive, releasing digested peptides intermediates that can be further cleaved subsequently (PubMed:24931469).
It is also able to degrade amyloid-beta protein 42 (PubMed:29764912).

Biological Process

Protein processingManual Assertion Based On ExperimentIBA:GO_Central
Protein targeting to mitochondrionTAS:Reactome
ProteolysisManual Assertion Based On ExperimentIDA:UniProtKB

Cellular Location

Mitochondrion
Mitochondrion matrix

Involvement in disease

Spinocerebellar ataxia, autosomal recessive, 30 (SCAR30):
A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR30 is a progressive disease characterized by childhood-onset global developmental delay with variably impaired intellectual development, motor dysfunction, and cerebellar ataxia. Affected individuals may also have psychiatric abnormalities.

PTM

A disulfide bond locks the enzyme in the closed conformation preventing substrate entry into the catalytic chamber.