# TMPRSS2 (Transmembrane Protease Serine 2): Spike Cleavage Activation and Host Cell Entry ## Key Takeaways - TMPRSS2 is a type II transmembrane serine protease critical for the entry of enveloped viruses, notably SARS-CoV-2, by cleaving the viral spike (S) glycoprotein at the S1/S2 and S2′ sites, a process essential for viral fusion with the host cell membrane. - The gene encoding TMPRSS2 is located on human chromosome 21q22.3 and is highly regulated by androgens via androgen response elements (AREs) in its promoter, leading to high expression in the prostate and significant implications in prostate cancer, particularly through TMPRSS2-ERG gene fusions. - Beyond viral activation, TMPRSS2 participates in the processing of host cell receptors like ACE2 and activates protease-activated receptor 2 (PAR2), influencing broader physiological processes including inflammation and tissue homeostasis. - Small-molecule inhibitors, such as camostat mesylate and nafamostat mesylate, which target the serine protease active site, have been investigated as broad-spectrum antivirals, though clinical efficacy for COVID-19 has been limited, necessitating further research into more specific inhibitors and delivery methods. - Genetic variations within the *TMPRSS2* gene, including common polymorphisms like rs12329760, can influence susceptibility to viral infections and potentially impact the response to TMPRSS2-targeted therapies. --- ## Executive Summary & Key Metadata TMPRSS2 (Transmembrane Protease Serine 2) is a type II transmembrane serine protease (TTSP) encoded on human chromosome 21q22.3. The enzyme is a principal molecular determinant of host cell susceptibility to multiple enveloped respiratory viruses, most notably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), where it performs the critical proteolytic cleavage of the viral spike (S) glycoprotein at the S1/S2 and S2′ sites. This cleavage event is a prerequisite for the fusion of the viral envelope with the host cell membrane and subsequent viral entry. Beyond its canonical role in viral pathogenesis, TMPRSS2 is a well-established androgen-regulated gene with significant implications in prostate cancer biology, where gene fusions (e.g., TMPRSS2-ERG) are among the most frequent genomic alterations in solid tumors. The enzyme also participates in the processing of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), and the protease-activated receptor 2 (PAR2), linking it to broader physiological processes including inflammation and tissue homeostasis. | **Attribute** | **Value** | |---|---| | **HGNC Symbol** | TMPRSS2 | | **UniProt Accession** | O15393 | | **Representative PDB ID** | 7MEQ | | **Chromosomal Locus** | 21q22.3 | | **Primary Molecular Function** | Serine-type endopeptidase activity; cleavage of viral glycoproteins and host substrates | | **Disease & Pathology Associations** | SARS-CoV-2 infection, influenza A virus infection, prostate cancer (gene fusions), androgenetic alopecia | --- ## 1. Genomic Locus, Chromosomal Organization & Isoforms ### 1.1 Gene Coordinates and Chromosomal Context The *TMPRSS2* gene is located on the long (q) arm of chromosome 21 at cytogenetic band 21q22.3. In the GRCh38/hg38 assembly, the gene spans approximately 33.5 kilobases (kb) of genomic DNA, from base pair 41,464,305 to 41,497,798 on the forward strand. The genomic locus is gene-dense, with the *TMPRSS2* gene situated in a region that also contains the *ERG* (ETS-related gene) oncogene approximately 3 megabases (Mb) telomeric. This proximity is of profound clinical significance, as androgen receptor (AR)-mediated transcriptional activity can induce a genomic rearrangement that fuses the androgen-responsive promoter of *TMPRSS2* with the coding sequence of *ERG*, resulting in the oncogenic TMPRSS2-ERG fusion gene. ### 1.2 Promoter Architecture and Transcriptional Regulation The *TMPRSS2* promoter is characterized by a canonical TATA box and a GC-rich region. The most distinctive regulatory feature is the presence of multiple androgen response elements (AREs) located both in the proximal promoter and in the first intron. These AREs are binding sites for the androgen receptor (AR), a ligand-activated nuclear transcription factor. Upon androgen binding, AR translocates to the nucleus, dimerizes, and binds to these AREs, recruiting coactivators such as steroid receptor coactivator-1 (SRC-1) and p300/CBP, which remodel chromatin and recruit [RNA polymerase](/knowledge/bioinformatics/rna-polymerase-structure-transcription-mechanisms) II. This androgen-dependent regulation is the basis for the high expression of TMPRSS2 in the prostate epithelium and for the use of androgen deprivation therapy (ADT) to reduce TMPRSS2 expression in prostate cancer. Beyond AR, the promoter contains binding sites for other transcription factors, including members of the ETS family (e.g., ETV1, ETV4), which can further modulate expression. The promoter also contains a CpG island, and its methylation status can influence transcriptional activity in a tissue-specific manner. In the lung, where TMPRSS2 is expressed at lower levels, the promoter is regulated by a distinct set of factors, including interferon regulatory factors (IRFs) and signal transducer and activator of transcription (STAT) proteins, which can be induced by inflammatory cytokines. ### 1.3 Enhancer Elements and Chromatin Architecture Chromatin immunoprecipitation followed by sequencing (ChIP-seq) studies have identified several enhancer elements within the *TMPRSS2* locus. A prominent enhancer is located approximately 10 kb upstream of the transcription start site (TSS), which is marked by histone H3 lysine 27 acetylation (H3K27ac) in prostate epithelial cells. This enhancer physically interacts with the promoter via chromatin looping, a process mediated by the cohesin complex and CCCTC-binding factor (CTCF). In lung tissue, a different set of enhancers may be active, reflecting the cell-type-specific regulation of the gene. The three-dimensional chromatin architecture of the locus is dynamic and can be altered by androgen signaling, which promotes a more open chromatin state conducive to transcription. ### 1.4 Alternative Splicing and Isoforms The *TMPRSS2* gene undergoes alternative splicing, generating multiple transcript variants. The canonical transcript (ENST00000398585) encodes the full-length 492-amino acid protein. However, several alternatively spliced isoforms have been documented: - **Isoform 1 (Canonical, 492 aa):** Contains the complete domain architecture: a short N-terminal cytoplasmic tail, a transmembrane domain, a LDL receptor class A (LDLRA) domain, a scavenger receptor cysteine-rich (SRCR) domain, and the C-terminal serine protease domain. - **Isoform 2 (Variant lacking exon 2):** This splice variant results in a protein that lacks the transmembrane domain, producing a soluble, secreted form of the protease. The biological significance of this isoform is under investigation, but it may act as a decoy or have altered substrate specificity. - **Isoform 3 (Variant lacking exon 10):** This variant produces a truncated protein that lacks a portion of the serine protease domain, likely resulting in a catalytically inactive protein. Its expression may be regulated in a tissue-specific manner. The regulation of alternative splicing is complex and involves the action of serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). The relative abundance of these isoforms can vary between tissues and in response to cellular stress or hormonal stimulation. --- ## 2. 3D Protein Domain Architecture & Structural Biology ### 2.1 Domain Organization The TMPRSS2 protein is a type II transmembrane serine protease, meaning its N-terminus is intracellular, and its C-terminus is extracellular. The full-length protein is 492 amino acids long and is organized into distinct functional domains: 1. **Cytoplasmic N-terminal domain (aa 1–84):** This short intracellular tail contains a potential internalization motif and sites for post-translational modification, though its precise function remains to be fully defined. It may play a role in intracellular trafficking and signaling. 2. **Transmembrane domain (aa 85–105):** A single-pass hydrophobic alpha-helix that anchors the protein to the plasma membrane. This domain is essential for the correct subcellular localization of the protease to the cell surface. 3. **Stem region (aa 106–242):** This extracellular region contains two protein-protein interaction modules: - **LDL receptor class A (LDLRA) domain (aa 106–146):** A ~40 amino acid domain that is homologous to the ligand-binding domain of the low-density lipoprotein receptor. It contains conserved cysteine residues that form disulfide bonds, stabilizing the domain structure. It is thought to mediate interactions with other membrane proteins or extracellular matrix components. - **Scavenger receptor cysteine-rich (SRCR) domain (aa 147–242):** A ~100 amino acid domain characterized by a conserved pattern of cysteine residues. SRCR domains are found in a variety of proteins involved in innate immunity and can mediate ligand binding. In TMPRSS2, this domain may contribute to substrate recognition or interaction with viral glycoproteins. 4. **Serine protease domain (aa 243–492):** The catalytic domain, which is homologous to trypsin-like serine proteases. It contains the canonical catalytic triad of histidine (His296), aspartate (Asp345), and serine (Ser441). The domain also contains three disulfide bonds that are critical for maintaining the active conformation. The substrate-binding pocket is specific for cleavage after basic amino acid residues (arginine or lysine), a hallmark of trypsin-like proteases. ### 2.2 Structural Insights from PDB: 7MEQ The representative structure for TMPRSS2, PDB ID 7MEQ, was solved by X-ray crystallography. This structure corresponds to the extracellular portion of the protein, encompassing the LDLRA, SRCR, and serine protease domains. The structure reveals a compact, elongated shape, with the stem domains extending from the membrane and positioning the protease domain for optimal access to substrates. The serine protease domain adopts a classic chymotrypsin-like fold, consisting of two six-stranded beta-barrel domains. The catalytic triad residues (His296, Asp345, Ser441) are positioned at the interface of the two barrels, forming a charge-relay system that is essential for peptide bond hydrolysis. The oxyanion hole, formed by the backbone amide groups of Gly439 and Ser441, stabilizes the tetrahedral intermediate during catalysis. The structure also reveals a key feature: the protease domain is synthesized as an inactive zymogen, requiring proteolytic cleavage between Arg255 and Ile256 to become fully active. This cleavage, which can be performed by other proteases or by autocatalysis, separates the pro-domain from the catalytic domain, inducing a conformational change that forms the mature active site. ### 2.3 Catalytic Mechanism The catalytic mechanism of TMPRSS2 follows the classical serine protease pathway. The reaction proceeds in two main steps: 1. **Acylation:** The substrate peptide binds in the active site, with the scissile bond positioned adjacent to the catalytic Ser441. The nucleophilic oxygen of Ser441 attacks the carbonyl carbon of the scissile bond, forming a tetrahedral intermediate. This intermediate is stabilized by the oxyanion hole. The imidazole group of His296 acts as a general base, accepting a proton from Ser441, and then as a general acid, donating a proton to the leaving group (the amine of the C-terminal fragment). This results in the formation of an acyl-enzyme intermediate. 2. **Deacylation:** A water molecule, activated by His296, attacks the acyl-enzyme intermediate, forming a second tetrahedral intermediate. This collapses to release the C-terminal product and regenerate the free enzyme. The specificity of TMPRSS2 for cleavage after arginine or lysine residues is dictated by the presence of a negatively charged aspartate residue (Asp435) at the bottom of the S1 specificity pocket, which forms a salt bridge with the positively charged side chain of the substrate's basic residue. ### 2.4 Interactive 3D Visualizer [Interactive 3D Protein Visualizer: Load TMPRSS2 (PDB: 7MEQ)](/tools/protein-structure-viewer?source=direct&pdbId=7MEQ) The interactive visualizer allows for the exploration of the TMPRSS2 structure in three dimensions. Users can rotate the molecule, zoom into the active site, and highlight specific domains or residues. This tool is invaluable for understanding the spatial arrangement of the catalytic triad, the substrate-binding pocket, and the potential allosteric sites that could be targeted by small-molecule inhibitors. --- ## 3. Cellular Signaling Pathways & Molecular Function ### 3.1 Proteolytic Processing of Viral Glycoproteins The primary and most extensively characterized function of TMPRSS2 is the proteolytic activation of viral envelope glycoproteins. This process is essential for the infectivity of several respiratory viruses, including: - **SARS-CoV-2:** The spike (S) glycoprotein of SARS-CoV-2 is a trimeric class I fusion protein. To mediate membrane fusion, the S protein must be cleaved at two sites: the S1/S2 site (between residues 685 and 686) and the S2′ site (between residues 815 and 816). TMPRSS2 cleaves at both sites. Cleavage at S1/S2 primes the protein, while cleavage at S2′ is the final trigger that releases the fusion peptide and drives the conformational change required for membrane fusion. This TMPRSS2-dependent entry pathway occurs at the plasma membrane, allowing for rapid viral entry. - **Influenza A virus (IAV):** The hemagglutinin (HA) glycoprotein of IAV is synthesized as a precursor (HA0) that must be cleaved by host proteases to become fusion-competent. TMPRSS2 is one of the key proteases that cleaves HA0 at a monobasic site, particularly for human seasonal influenza viruses. This cleavage is essential for viral entry into airway epithelial cells. - **Other coronaviruses:** TMPRSS2 also activates the spike proteins of SARS-CoV-1 and MERS-CoV, indicating a broad role in coronavirus entry. ### 3.2 Interaction with ACE2 TMPRSS2 not only cleaves the viral spike protein but also cleaves the host cell receptor ACE2. ACE2 is the primary receptor for SARS-CoV-2. TMPRSS2-mediated cleavage of ACE2 occurs at arginine residues within its ectodomain. This cleavage enhances viral entry by promoting the release of the ACE2 ectodomain, which may facilitate the accessibility of the receptor to the spike protein and promote membrane fusion. The cleavage of ACE2 by TMPRSS2 is a unique feature that distinguishes the TMPRSS2-dependent entry pathway from the endosomal cathepsin-dependent pathway. ### 3.3 Signaling via Protease-Activated Receptors (PARs) Beyond viral entry, TMPRSS2 can cleave and activate protease-activated receptor 2 (PAR2). PARs are G-protein-coupled receptors that are activated by proteolytic cleavage of their N-terminal extracellular domain, which exposes a tethered ligand that binds to the receptor's own extracellular loop. TMPRSS2-mediated activation of PAR2 can trigger downstream signaling cascades, including the activation of phospholipase C (PLC), which leads to the production of inositol trisphosphate (IP3) and diacylglycerol (DAG), and the subsequent release of intracellular calcium and activation of protein kinase C (PKC). This pathway can modulate inflammatory responses, cell proliferation, and tissue remodeling. ### 3.4 Role in Prostate Cancer and the Androgen Signaling Axis In the prostate, TMPRSS2 expression is directly regulated by the androgen receptor (AR). The AR signaling pathway is critical for the development and progression of prostate cancer. The most significant consequence of this androgen regulation is the occurrence of genomic rearrangements that fuse the 5′ untranslated region of *TMPRSS2* with the coding sequence of the ETS transcription factor *ERG*. The TMPRSS2-ERG fusion is present in approximately 50% of prostate cancers. This fusion places *ERG* under the control of the androgen-responsive *TMPRSS2* promoter, leading to the overexpression of the ERG oncoprotein in response to androgens. ERG overexpression drives a transcriptional program that promotes cell proliferation, invasion, and epithelial-to-mesenchymal transition (EMT). The TMPRSS2-ERG fusion is a key driver of prostate cancer pathogenesis and is a potential biomarker and therapeutic target. The fusion can be detected in urine samples, providing a non-invasive diagnostic tool. ### 3.5 Protein-Protein Interaction Networks TMPRSS2 participates in a complex network of protein-protein interactions. Key interacting partners include: - **Viral glycoproteins (Spike, HA):** Direct substrates. - **ACE2:** Substrate and receptor complex partner. - **PAR2:** Substrate and signaling initiator. - **Serine protease inhibitors (Serpins):** Endogenous inhibitors, such as hepatocyte growth factor activator inhibitor (HAI-1 and HAI-2), which regulate TMPRSS2 activity. - **Prostasin:** Another TTSP that can activate TMPRSS2 through proteolytic cleavage. These interactions are critical for the spatiotemporal regulation of TMPRSS2 activity. ```mermaid sequenceDiagram participant Virus as "SARS-CoV-2 Virion" participant Spike as "Spike (S) Glycoprotein" participant TMPRSS2 as "TMPRSS2 (Host Protease)" participant ACE2 as "ACE2 (Host Receptor)" participant Membrane as "Host Cell Membrane" Virus->>Spike: Present on viral surface Spike->>ACE2: Binds to ACE2 receptor ACE2->>TMPRSS2: Recruits TMPRSS2 to complex TMPRSS2->>Spike: Cleaves at S1/S2 and S2' sites Spike-->>Membrane: Conformational change, fusion peptide insertion Membrane->>Membrane: Membrane fusion Note over Membrane: Viral RNA released into cytoplasm ``` --- ## 4. Pathogenic Hotspot Mutations & Clinical Differentials ### 4.1 Common Polymorphisms and Their Impact Several single nucleotide polymorphisms (SNPs) have been identified in the *TMPRSS2* gene. One of the most studied is rs12329760, which results in a missense variant (p.Val160Met) located in the SRCR domain. This variant has been associated with altered susceptibility to SARS-CoV-2 infection and disease severity. The methionine variant is thought to alter the stability or substrate specificity of the protease, potentially reducing its efficiency in cleaving the spike protein. However, the clinical data are mixed, with some studies showing a protective effect and others showing no significant association. Another notable variant is rs2070788, located in an intronic region, which has been associated with differential expression of TMPRSS2 in lung tissue. This variant may influence the binding of transcription factors, thereby modulating gene expression and potentially affecting susceptibility to influenza and SARS-CoV-2. ### 4.2 Somatic Mutations in Cancer In prostate cancer, the most frequent alteration is the TMPRSS2-ERG gene fusion, which is a structural rearrangement rather than a point mutation. However, somatic point mutations within the *TMPRSS2* gene have also been identified in various cancers, though they are less common. These mutations can occur in the protease domain and may alter its catalytic activity. For example, mutations that disrupt the catalytic triad (e.g., Ser441 mutations) would result in a catalytically dead enzyme. The functional consequences of these mutations in the context of cancer are not fully understood, but they may affect the tumor microenvironment by altering the processing of growth factors or cytokines. ### 4.3 Pathogenic Variants and Clinical Phenotypes While germline pathogenic variants in *TMPRSS2* that cause a complete loss of function are rare, they have been studied for their impact on viral susceptibility. Individuals with rare loss-of-function variants may have reduced susceptibility to SARS-CoV-2 infection, as the virus would be unable to use the TMPRSS2-dependent entry pathway. However, no severe developmental or physiological phenotypes have been reported for such individuals, suggesting that TMPRSS2 is not essential for normal development or homeostasis, likely due to functional redundancy with other TTSPs. ### 4.4 Differential Diagnosis and Clinical Implications The clinical implications of TMPRSS2 alterations are primarily in the context of prostate cancer and infectious diseases. In prostate cancer, the presence of the TMPRSS2-ERG fusion is associated with a distinct molecular subtype of the disease. It is more common in younger patients and is often associated with a more aggressive tumor phenotype, although the prognostic significance is still debated. The fusion status can be used as a biomarker for diagnosis and risk stratification. In the context of infectious diseases, the expression level of TMPRSS2 in the respiratory tract is a key determinant of susceptibility to severe viral infections. High expression levels are associated with increased viral entry and more severe disease. This has led to the investigation of TMPRSS2 inhibitors as a therapeutic strategy. --- ## 5. Host-Pathogen & Viral Interactions ### 5.1 The SARS-CoV-2 Entry Mechanism The interaction between TMPRSS2 and the SARS-CoV-2 spike protein is the most critical host-pathogen interaction involving this protease. The entry process is a multi-step event: 1. **Receptor Binding:** The receptor-binding domain (RBD) of the spike protein binds to the peptidase domain of ACE2 on the host cell surface. 2. **Proteolytic Priming:** The binding of the spike to ACE2 likely induces a conformational change that exposes the S1/S2 cleavage site to TMPRSS2. TMPRSS2, which is co-localized with ACE2 on the plasma membrane, cleaves the spike at the S1/S2 site. This cleavage is essential for the subsequent steps. 3. **Fusion Trigger:** A second cleavage at the S2′ site by TMPRSS2 is required to activate the fusion machinery. This cleavage generates a new N-terminus on the S2 subunit, which includes the fusion peptide. The fusion peptide inserts into the host cell membrane, and the S2 subunit undergoes a dramatic conformational rearrangement, bringing the viral and host membranes into close apposition and driving their fusion. 4. **Genome Release:** The fusion pore expands, allowing the viral ribonucleoprotein complex to be released into the host cell cytoplasm. This TMPRSS2-dependent pathway is the primary route of entry for SARS-CoV-2 in airway epithelial cells. In cells with low TMPRSS2 expression, the virus can alternatively enter via the endosomal pathway, where cathepsins B and L perform the spike cleavage. However, the TMPRSS2 pathway is more efficient and is associated with a faster, more direct entry. ### 5.2 Influenza A Virus Activation For influenza A virus, TMPRSS2 cleaves the hemagglutinin (HA) protein. The HA protein is a trimer, and each monomer is synthesized as a single polypeptide precursor (HA0). Cleavage of HA0 into HA1 and HA2 is essential for the virus to be infectious. TMPRSS2 cleaves HA0 at a monobasic cleavage site (a single arginine residue) in the case of low-pathogenic [avian influenza](/knowledge/bacteria/avian-bacteria/avian-influenza-cdc-global-surveillance) and human seasonal influenza viruses. This cleavage primes the HA for the low-pH-triggered conformational change that occurs in the endosome, leading to membrane fusion. ### 5.3 Viral Evasion and Host Countermeasures Viruses do not typically evade TMPRSS2, as they depend on it for entry. However, the host has evolved countermeasures to regulate TMPRSS2 activity. The expression of TMPRSS2 is tightly regulated, and its activity is controlled by endogenous inhibitors, such as HAI-1 and HAI-2. Additionally, the host can modulate TMPRSS2 expression in response to viral infection through the action of interferons and other cytokines, although the exact mechanisms are still being investigated. ### 5.4 Other Viral Interactions TMPRSS2 has also been shown to activate the spike proteins of other coronaviruses, including SARS-CoV-1 and MERS-CoV, as well as the fusion proteins of other enveloped viruses, such as human metapneumovirus (HMPV). This broad substrate specificity highlights its central role in the entry of multiple respiratory viruses. --- ## 6. [Pharmacogenomics](/knowledge/bioinformatics/pharmacogenomics-tailoring-drugs-to-genetic-profiles), Drug Targets & Small-Molecule Inhibitors ### 6.1 TMPRSS2 as a Therapeutic Target The central role of TMPRSS2 in viral entry makes it an attractive target for antiviral therapy. Inhibiting TMPRSS2 would block the entry of SARS-CoV-2, influenza, and other respiratory viruses, providing a broad-spectrum antiviral strategy. Furthermore, because TMPRSS2 is a host protease, targeting it may be less prone to the development of drug resistance compared to targeting viral proteins. ### 6.2 Investigational Small-Molecule Inhibitors Several classes of small-molecule inhibitors have been investigated: - **Serine Protease Inhibitors:** The most extensively studied inhibitors are broad-spectrum serine protease inhibitors, such as **camostat mesylate** and **nafamostat mesylate**. These drugs are approved in Japan for the treatment of pancreatitis and other conditions. They act by forming a covalent, but reversible, complex with the serine residue in the active site of the protease. In vitro studies have shown that camostat and nafamostat effectively block TMPRSS2 activity and inhibit SARS-CoV-2 entry into lung cells. However, clinical trials have shown limited efficacy in treating COVID-19, likely due to the need for high local concentrations in the respiratory tract and the potential for alternative entry pathways. - **Specific TMPRSS2 Inhibitors:** More specific inhibitors are being developed to minimize off-target effects. These include peptidomimetic inhibitors that mimic the substrate sequence of TMPRSS2 and non-peptidic small molecules identified through high-throughput screening. Some of these compounds have shown potent and selective inhibition of TMPRSS2 in preclinical models. - **Natural Product Inhibitors:** Several natural compounds, such as **baicalein** and **quercetin**, have been identified as TMPRSS2 inhibitors, though their potency and specificity are generally lower than synthetic inhibitors. ### 6.3 Monoclonal Antibodies and Other Biologics Monoclonal antibodies targeting the TMPRSS2 protease domain are being explored. These antibodies could bind to the extracellular domain of TMPRSS2 and block its access to viral substrates. However, the development of such antibodies is challenging due to the need for high affinity and specificity. ### 6.4 Gene Therapy and RNA Interference RNA interference (RNAi) approaches, such as small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs), can be used to knock down TMPRSS2 expression. These approaches have been shown to reduce viral entry in vitro. However, the delivery of RNAi therapeutics to the respiratory tract remains a significant challenge. Gene therapy using CRISPR-Cas9 to disrupt the *TMPRSS2* gene is also being explored as a potential strategy, though this is a more long-term and complex approach. ### 6.5 Pharmacogenomic Considerations The efficacy of TMPRSS2 inhibitors may be influenced by genetic variation in the *TMPRSS2* gene. For example, individuals carrying the rs12329760 variant (p.Val160Met) may respond differently to inhibitors. Pharmacogenomic studies are needed to determine whether genotype-guided therapy could improve treatment outcomes. --- ## 7. Bioinformatic Resources & Database Accessions | **Database** | **Identifier** | **URL** | |---|---|---| | **NCBI Gene** | 7113 | [https://www.ncbi.nlm.nih.gov/gene/7113](https://www.ncbi.nlm.nih.gov/gene/7113) | | **Ensembl** | ENSG00000184012 | [https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000184012](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000184012) | | **UniProt** | O15393 | [https://www.uniprot.org/uniprotkb/O15393](https://www.uniprot.org/uniprotkb/O15393) | | **RCSB PDB** | 7MEQ | [https://www.rcsb.org/structure/7MEQ](https://www.rcsb.org/structure/7MEQ) | | **Gene Ontology (GO)** | GO:0004252 (serine-type endopeptidase activity), GO:0005886 (plasma membrane), GO:0016021 (integral component of membrane) | [https://www.ebi.ac.uk/QuickGO/](https://www.ebi.ac.uk/QuickGO/) | | **ClinVar** | Gene: TMPRSS2 | [https://www.ncbi.nlm.nih.gov/clinvar/?term=TMPRSS2](https://www.ncbi.nlm.nih.gov/clinvar/?term=TMPRSS2) | | **STRING** | O15393 | [https://string-db.org/network/9606.ENSP00000378310](https://string-db.org/network/9606.ENSP00000378310) | | **BioGRID** | 118309 | [https://thebiogrid.org/118309](https://thebiogrid.org/118309) | | **OMIM** | 602060 | [https://www.omim.org/entry/602060](https://www.omim.org/entry/602060) | --- ## Related Clinical & Scientific Guides * [DPP4 (CD26): MERS-CoV Receptor Attachment, Dipeptidyl Peptidase Activity, and Metabolic Tropism](/knowledge/bioinformatics/genes/virology-receptors/dpp4-gene-structure-function-pathway) * [ANPEP (CD13): Aminopeptidase N Structure and Coronavirus Receptor Attachment Mechanisms](/knowledge/bioinformatics/genes/virology-receptors/anpep-gene-structure-function-pathway) * [CCR5 Chemokine Receptor: HIV-1 Coreceptor Tropism, CCR5-Delta32 Mutation, and Entry Blockers](/knowledge/bioinformatics/genes/virology-receptors/ccr5-gene-structure-function-pathway) ## References 1. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., ... & Pöhlmann, S. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. *Cell*, 181(2), 271-280. [https://doi.org/10.1016/j.cell.2020.02.052](https://doi.org/10.1016/j.cell.2020.02.052) 2. Glowacka, I., Bertram, S., Müller, M. A., Allen, P., Soilleux, E., Pfefferle, S., ... & Pöhlmann, S. (2011). Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control in the lung. *Journal of Virology*, 85(9), 4122-4134. [https://doi.org/10.1128/JVI.02232-10](https://doi.org/10.1128/JVI.02232-10) 3. Shulla, A., Heald-Sargent, T., Subramanya, G., Zhao, J., Perlman, S., & Gallagher, T. (2011). A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. *Journal of Virology*, 85(2), 873-882. [https://doi.org/10.1128/JVI.02062-10](https://doi.org/10.1128/JVI.02062-10) 4. Tomlins, S. A., Rhodes, D. R., Perner, S., Dhanasekaran, S. M., Mehra, R., Sun, X. W., ... & Chinnaiyan, A. M. (2005). Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. *Science*, 310(5748), 644-648. [https://doi.org/10.1126/science.1117679](https://doi.org/10.1126/science.1117679) 5. Lucas, J. M., True, L., Hawley, S., Matsumura, M., Morrissey, C., Vessella, R., & Nelson, P. S. (2008). The androgen-regulated type II serine protease TMPRSS2 is differentially expressed and mislocalized in prostate adenocarcinoma. *The Journal of Pathology*, 215(2), 118-125. [https://doi.org/10.1002/path.2330](https://doi.org/10.1002/path.2330) 6. Bottcher, E., Matrosovich, T., Beyerle, M., Klenk, H. D., Garten, W., & Matrosovich, M. (2006). Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. *Journal of Virology*, 80(19), 9896-9898. [https://doi.org/10.1128/JVI.01118-06](https://doi.org/10.1128/JVI.01118-06) 7. Iwata-Yoshikawa, N., Okamura, T., Shimizu, Y., Hasegawa, H., Takeda, M., & Nagata, N. (2019). TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. *Journal of Virology*, 93(6), e01815-18. [https://doi.org/10.1128/JVI.01815-18](https://doi.org/10.1128/JVI.01815-18) 8. Laporte, M., & Naesens, L. (2017). Airway proteases: an emerging drug target for influenza and other respiratory virus infections. *Current Opinion in Virology*, 24, 16-24. [https://doi.org/10.1016/j.coviro.2017.03.018](https://doi.org/10.1016/j.coviro.2017.03.018) 9. Shen, L. W., Mao, H. J., Wu, Y. L., Tanaka, Y., & Zhang, W. (2017). TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. *Biochimie*, 142, 1-10. [https://doi.org/10.1016/j.biochi.2017.07.016](https://doi.org/10.1016/j.biochi.2017.07.016) 10. Fraser, B. J., Beldar, S., Seitova, A., Hutchinson, A., Mannar, D., Li, Y., ... & Benard, F. (2022). Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation. *Nature Chemical Biology*, 18(9), 963-971. [https://doi.org/10.1038/s41589-022-01059-7](https://doi.org/10.1038/s41589-022-01059-7)