title: Promiscuous processing of human alphabeta-protryptases by cathepsins L, B, and C.
abstract: Human α- and β-protryptase zymogens are abundantly and selectively produced by mast cells, but the mechanism(s) by which they are processed is uncertain. β-Protryptase is sequentially processed in vitro by autocatalysis at R(-3) followed by cathepsin (CTS) C proteolysis to the mature enzyme. However, mast cells from CTSC-deficient mice successfully convert protryptase (pro-murine mast cell protease-6) to mature murine mast cell protease-6. α-Protryptase processing cannot occur by trypsin-like enzymes due to an R(-3)Q substitution. Thus, biological mechanisms for processing these zymogens are uncertain. β-Tryptase processing activity(ies) distinct from CTSC were partially purified from human HMC-1 cells and identified by mass spectroscopy to include CTSB and CTSL. Importantly, CTSB and CTSL also directly process α-protryptase (Q(-3)) and mutated β-protryptase (R(-3)Q) as well as wild-type β-protryptase to maturity, indicating no need for autocatalysis, unlike the CTSC pathway. Heparin promoted tryptase tetramer formation and protected tryptase from degradation by CTSB and CTSL. Thus, CTSL and CTSB are capable of directly processing both α- and β-protryptases from human mast cells to their mature enzymatically active products.
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Quang T
authors.initials: QT
authors.lastname: Le
authors.forename: Hae-Ki
authors.initials: HK
authors.lastname: Min
authors.forename: Han-Zhang
authors.initials: HZ
authors.lastname: Xia
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukuoka
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Katunuma
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Schwartz
mesh_terms: D002401:Cathepsin B / Q000378:metabolism; D020789:Cathepsin C / Q000378:metabolism; D056668:Cathepsin L / Q000378:metabolism; D002403:Cathepsins / Q000032:analysis / Q000378:metabolism*; D002460:Cell Line; D004792:Enzyme Precursors / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D013058:Mass Spectrometry; D008407:Mast Cells / Q000201:enzymology* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D053802:Tryptases / Q000378:metabolism*
chemical_list: D004792:Enzyme Precursors; D006493:Heparin; D002403:Cathepsins; D020789:Cathepsin C; C509222:Tpsab1 protein, mouse; D053802:Tryptases; D002401:Cathepsin B; D056668:Cathepsin L