Prf1

Domain

Perforin consists of three domains: (1) the MACPF domain, which includes the central machinery of pore formation, (2) the EGF-like domain, which forms a 'shelf-like' assembly connecting the MACPF and C2 domains, and (3) the C2 domain, which mediates calcium-dependent binding to lipid membranes (PubMed:21037563, PubMed:35148176). The C2 domain is critical for initial calcium-dependent interaction with lipid membranes of the target cell: calcium-binding causes a significant structural rearrangement, leading to oligomerization and deployment of the two transmembrane beta-strands (named CH1/TMH1 and CH2/TMH2) that enter the membrane as amphipathic beta-hairpins (PubMed:21037563, PubMed:26306037, PubMed:35148176). The third calcium-binding site (Ca(2+) 3), which constitutes the weakest affinity site, triggers structural rearrangements in the C2 domain that facilitate its interaction with lipid membranes (PubMed:26306037).

Function

Pore-forming protein that plays a key role in granzyme-mediated programmed cell death, and in defense against virus-infected or neoplastic cells (PubMed:19446473, PubMed:21037563, PubMed:26306037, PubMed:2783478, PubMed:3261391, PubMed:35148176, PubMed:35705808, PubMed:7520535, PubMed:7526382, PubMed:7972104, PubMed:8164737). Can insert into the membrane of target cells in its calcium-bound form, oligomerize and form large pores (PubMed:19446473, PubMed:21037563, PubMed:26306037, PubMed:3261391, PubMed:35148176, PubMed:35705808, PubMed:7526382, PubMed:8164737). Promotes cytolysis and apoptosis of target cells by mediating the passage and uptake of cytotoxic granzymes (PubMed:19446473, PubMed:21037563, PubMed:26306037, PubMed:3261391, PubMed:35148176, PubMed:7526382, PubMed:8164737). Facilitates the delivery of cationic cargo protein, while anionic or neural proteins are not delivered efficiently (By similarity). Perforin pores allow the release of mature caspase-7 (CASP7) into the extracellular milieu (PubMed:35705808).

Post-translational modifications

N-glycosylated. The glycosylation sites are facing the interior of the pore.

Sequence Similarities

Belongs to the complement C6/C7/C8/C9 family.

Tissue Specificity

Detected in cytotoxic T-lymphocytes and natural killer cells.

Cellular localization

• Cytolytic granule
• Secreted
• Cell membrane
• Multi-pass membrane protein
• Endosome lumen
• Released from cytotoxic lymphocytes, together with proapoptotic granzymes: stored in cytolytic granules of cytolytic T-lymphocytes and secreted into the cleft between T-lymphocyte and target cell (PubMed:2040805, PubMed:8164737). May be taken up via endocytosis involving clathrin-coated vesicles and accumulate in a first time in large early endosomes (By similarity). Inserts into the cell membrane of target cells and forms pores (PubMed:19446473, PubMed:21037563). Membrane insertion and pore formation requires a major conformation change (PubMed:19446473, PubMed:21037563).

Alternative names

Pfp, Prf1, Perforin-1, P1, Cytolysin, Lymphocyte pore-forming protein

Database links

swissprot:P10820 entrezGene:18646

Other research areas

• Immunology & Infectious Disease