Download MendeleyIdentification of SERPINB1 as a physiological inhibitor of human granzyme H
Wang, L., Li, Q., Wu, L., Liu, S., Zhang, Y., Yang, X., Zhu, P., Zhang, H., Zhang, K., Lou, J., Liu, P., Tong, L., Sun, F., Fan, Z.(2013) J Immunol 190: 1319-1330
- PubMed: 23269243
- DOI: https://doi.org/10.4049/jimmunol.1202542
- Primary Citation of Related Structures:
4GA7, 4GAW - PubMed Abstract:
The granzyme/perforin pathway is a major mechanism for cytotoxic lymphocytes to eliminate virus-infected and tumor cells. The balance between activation and inhibition of the proteolytic cascade must be tightly controlled to avoid self damage. Granzyme H (GzmH) is constitutively expressed in NK cells and induces target cell death; however, how GzmH activity is regulated remains elusive. We reported earlier the crystal structures of inactive D102N-GzmH alone and in complex with its synthetic substrate and inhibitor, as well as defined the mechanisms of substrate recognition and enzymatic activation. In this study, we identified SERPINB1 as a potent intracellular inhibitor for GzmH. Upon cleavage of the reactive center loop at Phe(343), SERPINB1 forms an SDS-stable covalent complex with GzmH. SERPINB1 overexpression suppresses GzmH- or LAK cell-mediated cytotoxicity. We determined the crystal structures of active GzmH and SERPINB1 (LM-DD mutant) in the native conformation to 3.0- and 2.9-Å resolution, respectively. Molecular modeling reveals the possible conformational changes in GzmH for the suicide inhibition. Our findings provide new insights into the inhibitory mechanism of SERPINB1 against human GzmH.
Organizational Affiliation:
Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
