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TRYPSIN DOMAIN-CONTAINING PROTEIN 1; TYSND1

TRYPSIN DOMAIN-CONTAINING PROTEIN 1; TYSND1

HGNC Approved Gene Symbol: TYSND1Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38): 10:70,137,980-70,146,699 (from NCBI)▼ DescriptionAll peroxisomal...

HGNC Approved Gene Symbol: TYSND1

Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38): 10:70,137,980-70,146,699 (from NCBI)

▼ Description
All peroxisomal proteins are synthesized in the cytosol, and 2 distinct peroxisomal targeting signals (PTSs), the C-terminal PTS1 and N-terminal PTS2, are used for transport of these proteins into peroxisomes. Proteolytic cleavage of the N-terminal targeting sequence of PTS2 proteins accompanies import into peroxisomes, and many PTS1 proteins undergo C-terminal processing once in the peroxisomal matrix. TYSND1 processes both PTS1 and PTS2 proteins involved in beta-oxidation of fatty acids (Kurochkin et al., 2007).

▼ Cloning and Expression
By database analysis, Kurochkin et al. (2005) identified mouse Tysnd1 and its rat and human homologs. The mouse Tysnd1 protein has a PTS1 motif and 2 protease-related domains.

Kurochkin et al. (2007) stated that mouse Tysnd1 contains 568 amino acids and has 2 trypsin-like serine and cysteine peptidase domains. Western blot analysis of transfected COS-7 cells revealed a 59-kD protein corresponding to full-length recombinant Tysnd1 and a 49-kD protein representing the processed form. Fractionation of rat liver homogenate and Western blot analysis showed that endogenous Tysnd1 was synthesized as a 59-kD protein and converted to 49- and 27-kD forms following import into peroxisomes. Confocal microscopy localized Tysnd1 to peroxisomes of transfected Chinese hamster ovary cells.

By RT-PCR, Okumoto et al. (2011) cloned TYSND1 from normal human skin fibroblast mRNA. The deduced 566-amino acid protein has a serine protease domain with the conserved catalytic triad of his372, asp408, and ser481, and a C-terminal PTS1 peroxisome-targeting motif (SKL). Immunohistochemical analysis localized endogenous TYSND1 in peroxisomes in HEK293 cells. Database analysis detected orthologs of TYSND1 in vertebrate, insect, and plant, and in some yeast.

▼ Gene Function
Kurochkin et al. (2007) showed that mouse Tysnd1 processed the PTS2-containing peroxisomal precursor 3-oxoacyl-CoA thiolase (prethiolase, or ACAA1; 604054) and several PTS1-containing peroxisomal enzymes, including peroxisomal acyl-CoA oxidase (ACOX1; 609751), to their mature forms in transfected COS-7 cells. Small interfering RNA-mediated downregulation of TYSND1 in human embryonic kidney cells blocked processing of these peroxisomal enzymes. Additional studies showed that Tysnd1 directly processed peroxisomal enzymes in vitro, including prethiolase, which it cleaved between cys26 and ser27 to produce the mature form observed in vivo. Tysnd1 processing activity was abolished by N-ethylmaleimide, an inhibitor of cysteine proteinases. Kurochkin et al. (2007) determined that Tysnd1 itself is cleaved between cys110 and ala111, presumably removing an inhibitory N-terminal fragment.

Okumoto et al. (2011) found that human TYSND1 proteolytically processed peroxisomal enzymes of fatty acid beta-oxidation from their precursor form to their mature form, and that ser481 in TYSND1 was required for conversion activity. TYSND1 also proteolytically inactivated itself via cleavage between N-terminal residues cys110 and ala111. PSLON (617774), another peroxisomal matrix protease, interacted with TYSND1 and degraded the TYSND1 fragments after its autoinactivation. TYSND1 formed homooligomeric complexes consisting of the full-length proteins, full-length proteins bound to C-terminal fragments, and C-terminal fragments alone. Okumoto et al. (2011) concluded that TYSND1 has a major role in activating enzymes of peroxisomal fatty acid beta-oxidation.

▼ Mapping
The International Radiation Hybrid Mapping Consortium mapped the TYSND1 gene to chromosome 10 (D10S1466).

Tags: 10q22.1