Identification of SERPINB1 as a physiological inhibitor of human granzyme H.
J Immunol
; 190(3): 1319-30, 2013 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-23269243
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Serpinas
/
Granzimas
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Immunol
Año:
2013
Tipo del documento:
Article
País de afiliación:
China