title: Conformational dynamics of cancer-associated MyD88-TIR domain mutant L252P (L265P) allosterically tilts the landscape toward homo-dimerization.
abstract: MyD88 is an essential adaptor protein, which mediates the signaling of the toll-like and interleukin-1 receptors' superfamily. The MyD88 L252P (L265P) mutation has been identified in diffuse large B-cell lymphoma. The identification of this mutation has been a major advance in the diagnosis of patients with aldenstrom macroglobulinemia and related lymphoid neoplasms. Here we used computational methods to characterize the conformational effects of the mutation. Our molecular dynamics simulations revealed that the mutation allosterically quenched the global conformational dynamics of the toll/IL-1R (TIR) domain, and readjusted its salt bridges and dynamic community network. Specifically, the mutation changed the orientation and reduced the fluctuation of α-helix 3, possibly through eliminating/weakening ~8 salt bridges and enhancing the salt bridge D225-K258. Using the energy landscape of the TIR domains of MyD88, we identified two dynamic conformational basins, which correspond to the binding sites used in homo- and hetero-oligomerization, respectively. Our results indicate that the mutation stabilizes the core of the homo-dimer interface of the MyD88-TIR domain, and increases the population of homo-dimer-compatible conformational states in MyD88 family proteins. However, the dampened motion restricts its ability to heterodimerize with other TIR domains, thereby curtailing physiological signaling. In conclusion, the L252P both shifts the landscape toward homo-dimerization and restrains the dynamics of the MyD88-TIR domain, which disfavors its hetero-dimerization with other TIR domains. We further put these observations within the framework of MyD88-mediated cell signaling.
authors: State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), Department of Physics, Fudan University, Shanghai, P. R. China.
authors: Chendi
authors: C
authors: Zhan
authors: State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), Department of Physics, Fudan University, Shanghai, P. R. China.
authors: Ruxi
authors: R
authors: Qi
authors: State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), Department of Physics, Fudan University, Shanghai, P. R. China ghwei@fudan.edu.cn mabuyong@mail.nih.gov.
authors: Guanghong
authors: G
authors: Wei
authors: Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
authors: Emine
authors: E
authors: Guven-Maiorov
authors: Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Sackler Institute of Molecular Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors: Ruth
authors: R
authors: Nussinov
authors: Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA ghwei@fudan.edu.cn mabuyong@mail.nih.gov.
authors: Buyong
authors: B
authors: Ma
mesh_terms: D000494:Allosteric Regulation; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D025341:Principal Component Analysis; D000072417:Protein Domains; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D015398:Signal Transduction
chemical_list: D053594:Myeloid Differentiation Factor 88
keywords: MyD88; TIR domain; TLR; inflammation; protein dynamics