Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/161397
Title: Structural and biochemical mechanisms of NLRP1 inhibition by DPP9
Authors: Huang, Menghang
Zhang, Xiaoxiao
Toh, Gee Ann
Gong, Qin
Wang, Jia
Han, Zhifu
Wu, Bin
Zhong, Franklin
Chai, Jijie
Keywords: Science::Biological sciences
Issue Date: 2021
Source: Huang, M., Zhang, X., Toh, G. A., Gong, Q., Wang, J., Han, Z., Wu, B., Zhong, F. & Chai, J. (2021). Structural and biochemical mechanisms of NLRP1 inhibition by DPP9. Nature, 592(7856), 773-777. https://dx.doi.org/10.1038/s41586-021-03320-w
Project: MOH-000382-00 to W.B. 
NRF-NRFF11-2019-0006 to F.L.Z. 
Journal: Nature 
Abstract: Nucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find domain (FIIND)1-7. In resting cells, the dipeptidyl peptidases DPP8 and DPP9 interact with the FIIND of NLRP1 and suppress spontaneous NLRP1 activation8,9; however, the mechanisms through which this occurs remain unknown. Here we present structural and biochemical evidence that full-length rat NLRP1 (rNLRP1) and rat DPP9 (rDPP9) form a 2:1 complex that contains an autoinhibited rNLRP1 molecule and an active UPA-CARD fragment of rNLRP1. The ZU5 domain is required not only for autoinhibition of rNLRP1 but also for assembly of the 2:1 complex. Formation of the complex prevents UPA-mediated higher-order oligomerization of UPA-CARD fragments and strengthens ZU5-mediated NLRP1 autoinhibition. Structure-guided biochemical and functional assays show that both NLRP1 binding and enzymatic activity are required for DPP9 to suppress NLRP1 in human cells. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on the activation of the NLRP1 inflammasome.
URI: https://hdl.handle.net/10356/161397
ISSN: 0028-0836
DOI: 10.1038/s41586-021-03320-w
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
School of Biological Sciences 
Research Centres: Institute of Structural Biology 
Rights: © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles
SBS Journal Articles

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