9k1s
Crystal structure of human granzyme A in complex with GSDMB-C domain
Structural highlights
FunctionGRAA_HUMAN This enzyme is necessary for target cell lysis in cell-mediated immune responses. It cleaves after Lys or Arg. Cleaves APEX1 after 'Lys-31' and destroys its oxidative repair activity. Involved in apoptosis.[1] Publication Abstract from PubMedIn cellular immunity, cytotoxic lymphocytes employ granzyme A (GZMA) to cleave and activate the pore-forming protein gasdermin B (GSDMB) for the pyroptotic killing of target cells. How GZMA recognizes and cleaves GSDMB is unknown. Here, we show that human GZMA targets GSDMB via specific, high-affinity binding to its autoinhibitory GSDMB-C domain. This binding requires the dimerization of GZMA, a unique property among human granzymes. A crystal structure of the GZMA-GSDMB-C complex shows a 2:2 stoichiometry, featuring an exosite at each of the two symmetric dimer interfaces in GZMA. The exosite engages a two-loop-organized site in the GSDMB-C domain, rendering a functional cleavage at Lys244 in GSDMB. Mouse GZMA (mGZMA) adopts a similar dimer structure, but its exosite is less efficient in engaging GSDMB. Mutation of the exosite enabled mGZMA to efficiently cleave and activate GSDMB. Our study reveals a substrate-targeting mechanism used by lymphocyte-derived granzymes to kill target cells. Exosite-mediated targeting of GSDMB by dimeric granzyme A in lymphocyte pyroptotic killing.,Zhong X, Su Y, Zhou Z, Sun Y, Hou Y, Shao F, Ding J Immunity. 2026 Feb 10;59(2):257-269.e6. doi: 10.1016/j.immuni.2025.12.009. Epub , 2026 Jan 26. PMID:41592574[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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