Transmembrane protease serine 2

Protease activity

TMPRSS2, as a serine protease, cleaves peptide bonds present after positively charged residues (lysine or arginine). The main player in the catalytic mechanism is the catalytic triad formed by His296, Asp345, and Ser441. This three aminoacids are located in the active site of the enzyme. ^[2]

The substrate specificity is achieved with the presence of a negatively charged Asp residue at the bottom of a cavity usually indicated as “S1 specificity pocket”. ^[3]

General function

In terms of normal function, TMPRSS2 has been associated with physiological and pathological processes such as digestion, tissue remodelling, blood coagulation, fertility, inflammatory responses, tumour cell invasion, apoptosis and pain. ^[4]

Prostate cancer

Prostate cancer (PC) is the most common form of cancer found in American men and the second leading cause of cancer death. ^[5]

The most common chromosomal aberration causing this pathology is the fusion of the the promoter of transmembrane protease, serine 2 (TMPRSS2) gene and the coding sequence of the erythroblastosis virus E26 (Ets) gene family members. Ets family members are oncogenic transcription factors. Therefore, the fusion of these genes leads to the production of Ets transcription factors under the control of the androgen sensitive promoter elements of TMPRSS2.

The most common of these fusions is with ERG (erythroblast-specific-related gene), a member of the Ets family, resulting in the TMPRSS2-ERG fusion. The TMPRSS2-ERG fusion has been identified in approximately 50% of PC cases.

Viral entry

Structure

Gene

The TMPRSS2 gene resides on chromosome 21 at the band 21q22.3, and is split into 15 exons. It has an open reading frame of 492 amino acids.

This gene is conserved in a wide variety of animals, such as chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, Caenorhabditis elegans and frog.

Protein

TPMRSS2 is defined by the presence of an N-terminal cytoplasmic domain, a transmembrane helical domain, and three extracellular domains: ^[6]

• Low-density lipoprotein (LDL)-receptor class A domain
• Scavenger receptor cysteine-rich domain (SRCR)
• Peptidase S1 domain, also known as serine protease domain (SPD)

Expression

Phamacological therapeutic approaches

Structural highlights

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