title: Conformation switching of AIM2 PYD domain revealed by NMR relaxation and MD simulation.
abstract: Protein absent in melanoma 2 (AIM2) is a double-strand DNA (ds DNA) sensor mainly located in cytoplasm of cell. It includes one N terminal PYD domain and one C terminal HIN domain. When the ds DNA such as DNA viruses and bacteria entered cytoplasm, the HIN domain of AIM2 will recognize and bind to DNA, and the PYD domain will bind to ASC protein which will result in the formation of AIM2 inflammasome. Three AIM2 PYD domain structures have been solved, but every structure yields a unique conformation around the α3 helix region. To understand why different AIM2 PYD structures show different conformations in this region, we use NMR relaxation techniques to study the backbone dynamics of mouse AIM2 PYD domain and perform molecular dynamics (MD) simulations on both mouse and human AIM2 PYD structures. Our results indicate that this region is highly flexible in both mouse and human AIM2 PYD domains, and the PYD domain may exist as a conformation ensemble in solution. Different environment makes the population vary among pre-existing conformational substrates of the ensemble, which may be the reason why different AIM2 PYD structures were observed under different conditions. Further docking analysis reveals that the conformation switching may be important for the autoinhibition of the AIM2 protein.
authors.affiliation: College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
authors.forename: Haobo
authors.initials: H
authors.lastname: Wang
authors.affiliation: College of Chemistry and Molecular Engineering, Peking University, Beijing, China; Biodynamic Optical Imaging Center, Peking University, Beijing, China. Electronic address: yanglj@pku.edu.cn.
authors.forename: Lijiang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing, China; College of Chemistry and Molecular Engineering, Peking University, Beijing, China. Electronic address: niuxg@pku.edu.cn.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Niu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry*; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: C410167:AIM2 protein, human; C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins
keywords: AIM2; Conformation exchange; MD; NMR; PYD