Posttranslational modifications of serine protease TMPRSS13 regulate zymogen activation,proteolytic activity,and cell surface localization |
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Authors: | Carly E. Martin Andrew S. Murray Kimberley E. Sala-Hamrick Jacob R. Mackinder Evan C. Harrison Joseph G. Lundgren Fausto A. Varela Karin List |
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Affiliation: | 1.Department of Pharmacology, Wayne State University, Detroit, Michigan, USA;2.Department of Oncology, Wayne State University, Detroit, Michigan, USA;3.Division of Hematological Malignancies and Cellular Therapy, Duke University, Durham, North Carolina, USA;4.Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA |
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Abstract: | TMPRSS13, a member of the type II transmembrane serine protease (TTSP) family, harbors four N-linked glycosylation sites in its extracellular domain. Two of the glycosylated residues are located in the scavenger receptor cysteine-rich (SRCR) protein domain, while the remaining two sites are in the catalytic serine protease (SP) domain. In this study, we examined the role of N-linked glycosylation in the proteolytic activity, autoactivation, and cellular localization of TMPRSS13. Individual and combinatory site-directed mutagenesis of the glycosylated asparagine residues indicated that glycosylation of the SP domain is critical for TMPRSS13 autoactivation and catalytic activity toward one of its protein substrates, the prostasin zymogen. Additionally, SP domain glycosylation-deficient TMPRSS13 displayed impaired trafficking of TMPRSS13 to the cell surface, which correlated with increased retention in the endoplasmic reticulum. Importantly, we showed that N-linked glycosylation was a critical determinant for subsequent phosphorylation of endogenous TMPRSS13. Taken together, we conclude that glycosylation plays an important role in regulating TMPRSS13 activation and activity, phosphorylation, and cell surface localization. |
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Keywords: | serine protease N-linked glycosylation phosphorylation cell surface protein protease inhibitor type II transmembrane serine protease TTSP TMPRSS13 HAI-2 |
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