Choi Jae Young, Kim Chang Min, Seo Eun Kyung, Bhat Eijaz Ahmed, Jang Tae-Ho, Lee Jun Hyuck, Park Hyun Ho
School of Biotechnology and Graduate School of Biochemistry at Yeungnam University, Gyeongsan 712-749, South Korea.
Division of Polar Life Sciences, Korea Polar Research Institute, Incheon 406-840, Republic of Korea; Department of Polar Sciences, Korea University of Science and Technology, Incheon 406-840, Republic of Korea.
Biochem Biophys Res Commun. 2015 May 15;460(4):957-63. doi: 10.1016/j.bbrc.2015.03.134. Epub 2015 Apr 1.
Inflammatory caspases, such as caspase-1, which is critical for the innate immune response, are activated upon the formation of a molecular complex called the inflammasome. The inflammasome is composed of three proteins, the Nod-like receptor (NLRP, NLRC or AIM2), apoptosis associated speck-loke protein containing a caspase-recruitment domain (ASC), and caspase-1. ASC is an adaptor molecule that contains an N-terminal PYD domain and a C-terminal CARD domain for interaction with other proteins. Upon activation, the N-terminal PYD of ASC homotypically interacts with the PYD domain of the Nod-like receptor, while its C-terminal CARD homotypically interacts with the CARD domain of caspase-1. PYD only protein 1 (POP1) negatively regulates inflammatory response by blocking the formation of the inflammasome. POP1 directly binds to ASC via a PYD:PYD interaction, thereby preventing ASC recruitment to Nod-like receptor NLRPs. POP1-mediated regulation of inflammation is of great biological importance. Here, we report the crystal structure of human POP1 and speculate about the inhibitory mechanism of POP1-mediated inflammasome formation based on the current structure.
炎性半胱天冬酶，如对先天免疫反应至关重要的半胱天冬酶 -1，在一种称为炎性小体的分子复合物形成时被激活。炎性小体由三种蛋白质组成，即核苷酸结合寡聚化结构域样受体（NLRP、NLRC 或 AIM2）、含有半胱天冬酶募集结构域的凋亡相关斑点样蛋白（ASC）和半胱天冬酶 -1。ASC 是一种衔接分子，包含一个用于与其他蛋白质相互作用的 N 端吡咯结构域（PYD）和一个 C 端胱天蛋白酶激活和募集结构域（CARD）。激活后，ASC 的 N 端 PYD 与核苷酸结合寡聚化结构域样受体的 PYD 结构域同源性相互作用，而其 C 端 CARD 与半胱天冬酶 -1 的 CARD 结构域同源性相互作用。仅含 PYD 蛋白 1（POP1）通过阻断炎性小体的形成来负向调节炎症反应。POP1 通过 PYD:PYD 相互作用直接与 ASC 结合，从而阻止 ASC 募集到核苷酸结合寡聚化结构域样受体 NLRP 上。POP1 介导的炎症调节具有重要的生物学意义。在此，我们报道了人 POP1 的晶体结构，并基于当前结构推测了 POP1 介导炎性小体形成的抑制机制。
