Active monomers of human β-tryptase have expanded substrate specificities

Abstract

Abstractβ-Tryptase, a product of the TPSAB1 and TPSB2 genes, is a trypsin-like serine protease that is a major and selective component of the secretory granules of all human mast cells, accounting for as much as 25% of cell protein. Once mast cells are activated, β-tryptase is released along with histamine and heparin proteoglycan. β-Tryptase is a unique enzyme with a homotetrameric structure in which active sites face into the central cavity of the four monomers, stabilized by heparin-proteoglycan. This structure makes β-tryptase resistant to most biological inhibitors of serine proteases. Without stabilization, at neutral pH β-tryptase converts to inactive monomers. Tryptase levels are elevated in bronchoalveolar lavage (BAL) fluid obtained from atopic asthmatics and in serum during systemic anaphylactic shock. Several synthetic small molecular weight β-tryptase inhibitors reduced Aginduced airway hypersensitivity in animals, suggesting β-tryptase is involved in the pathogenesis of airway inflammation. Although the major biologic substrate(s) of β-tryptase remain ambiguous, the protease can digest several proteins of potential biologic importance, including fibrinogen, fibronectin, pro-urokinase, pro-matrix metalloprotease-3 (proMMP-3), protease activated receptor-2 (PAR2) and complement component C3. Recently, monomers of β-tryptase with enzymatic activity have been detected in vitro. Here we discuss how β-tryptase monomers with enzymatic activity were identified as well as their potential role in vivo.

An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

“…To see whether inhibition was simply due to a shift in pH optimum or a change in substrate specificity, we determined bI-tryptase activity at physiological heparin levels ($1 mg/mL) and found that anti-tryptase was also a potent and complete inhibitor at pH 7.0 and 8.0 ( Figure S3B). However, there was a small amount of residual activity at pH 6.0 from monomers that was inhibited by aprotinin ( Figure S3B), in accord with previous data (Fajardo and Pejler, 2003;Fukuoka and Schwartz, 2004;Fukuoka and Schwartz, 2007). However, monomers are $50-fold less active than tetramers at neutral pH and strongly dependent upon heparin (Maun et al, 2018) and rapidly inactivated by protease inhibitors (Fukuoka and Schwartz, 2004), thus thought not to be physiologically relevant.…”

Impact of Age and Heterophilic Interference on the Basal Serum Tryptase, a Risk Indication for Anaphylaxis, in 1,092 Dermatology Patients

“…In addition, we did not systematically evaluate other potential reasons for increased ST levels, such as diverse haematological disorders (e.g. acute myeloid leukaemia) (23,35), haemodialysis (36), or other allergic conditions, such as chronic urticaria (37) or anaphylactic reactions, which cause transient elevation of ß-tryptase (38). The extent of infiuence of these conditions in our population remains unclear.…”

Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion

“…These enzymes are locally activated and released into the microenvironment, where they can act on the various extracellular targets, i.e. activate pro-MMPs, cleave extracellular peptides and degrade lipoproteins and fibronectin [92]. Circulating tryptase levels are positively correlated with subclinical atherosclerosis and have a positive correlation with obesity and insulin resistance [93].…”