[3] The enzyme is initially in an inactive precursor zymogen form, with an additional amino terminal peptide sequence.
[2] Granzyme B contains the catalytic triad histidine-aspartic acid-serine in its active site and preferentially cleaves after an aspartic acid residue situated in the P1 position.
The enzyme is also rendered inactive when bound by serglycin in the granules to avoid apoptosis triggering inside the cytotoxic T cells themselves.
[4] Granzyme B is released with perforin which inserts into a target cell's plasma membrane forming a pore.
Alternatively, once released, granzyme B can bind to negatively charged heparan sulphate containing receptors on a target cell and become endocytosed.
[1] Granzyme B has a potential of over 300 substrates and can cleave Mcl-1 in the outer mitochondrial membrane relieving its inhibition of Bim.
[2] Granzyme B can also generate a cytotoxic level of mitochondrial reactive oxygen species (ROS) to mediate cell death.
[5] Basophils secrete granzyme B to degrade endothelial cell-cell contacts allowing extravasation to sites of inflammation.
[10] Cleavage of vitronectin occurs at the RGD integrin binding site interrupting cell growth signalling pathways.
Cleavage of laminin and fibronectin disrupts dermal-epidermal junction attachment and cross talk while decorin destruction by granzyme B causes collagen disorganisation, skin thinning and aging.
Cleavage of the von Willebrand factor inhibits platelet aggregation and of plasminogen produces an angiostatin fragment preventing angiogenesis.
The cutting of fibronectins and vitronectins delays the formation of a provisional matrix impairing wound healing further.
The reactive loop centre (RCL) of the PI-9 molecule acts as a pseudosubstrate and initially forms a reversible Michaelis complex.
Granzyme B can also mediate the death of cells after spinal cord injury and is found at elevated levels in rheumatoid arthritis.
The weakening of the fibrous cap of atheromatous plaques by apoptosis of smooth muscle cells has also been linked to granzyme B.