7JN7

Human DPP9-CARD8 complex

Summary for 7JN7

• Entry DOI: 10.2210/pdb7jn7/pdb
• EMDB information: 22402
• Descriptor: Dipeptidyl peptidase 9, Caspase recruitment domain-containing protein 8, [(2~{R})-1-[(2~{R})-2-azanyl-3-methyl-butanoyl]pyrrolidin-2-yl]boronic acid (3 entities in total)
• Functional Keywords: card8, dpp9, inflammasome, val-boropro (vbp), talabostat, innate immunity, immune system, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 325385.86

Authors

Sharif, H.,Hollingsworth, L.R. (deposition date: 2020-08-04, release date: 2021-05-19, Last modification date: 2024-10-23)

Primary citation

Sharif, H.,Hollingsworth, L.R.,Griswold, A.R.,Hsiao, J.C.,Wang, Q.,Bachovchin, D.A.,Wu, H.
Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment.
Immunity, 54:1392-, 2021

PubMed Abstract: CARD8 detects intracellular danger signals and forms a caspase-1 activating inflammasome. Like the related inflammasome sensor NLRP1, CARD8 autoprocesses into noncovalently associated N-terminal (NT) and C-terminal (CT) fragments and binds the cellular dipeptidyl peptidases DPP8 and 9 (DPP8/9). Certain danger-associated signals, including the DPP8/9 inhibitor Val-boroPro (VbP) and HIV protease, induce proteasome-mediated NT degradation and thereby liberate the inflammasome-forming CT. Here, we report cryoelectron microscopy (cryo-EM) structures of CARD8 bound to DPP9, revealing a repressive ternary complex consisting of DPP9, full-length CARD8, and CARD8-CT. Unlike NLRP1-CT, CARD8-CT does not interact with the DPP8/9 active site and is not directly displaced by VbP. However, larger DPP8/9 active-site probes can directly weaken this complex in vitro, and VbP itself nevertheless appears to disrupt this complex, perhaps indirectly, in cells. Thus, DPP8/9 inhibitors can activate the CARD8 inflammasome by promoting CARD8 NT degradation and by weakening ternary complex stability.

PubMed: 34019797
DOI: 10.1016/j.immuni.2021.04.024

Experimental method

ELECTRON MICROSCOPY (3.3 Å)