title: Mutation-induced protein interaction kinetics changes affect apoptotic network dynamic properties and facilitate oncogenesis.
abstract: It has been a consensus in cancer research that cancer is a disease caused primarily by genomic alterations, especially somatic mutations. However, the mechanism of mutation-induced oncogenesis is not fully understood. Here, we used the mitochondrial apoptotic pathway as a case study and performed a systematic analysis of integrating pathway dynamics with protein interaction kinetics to quantitatively investigate the causal molecular mechanism of mutation-induced oncogenesis. A mathematical model of the regulatory network was constructed to establish the functional role of dynamic bifurcation in the apoptotic process. The oncogenic mutation enrichment of each of the protein functional domains involved was found strongly correlated with the parameter sensitivity of the bifurcation point. We further dissected the causal mechanism underlying this correlation by evaluating the mutational influence on protein interaction kinetics using molecular dynamics simulation. We analyzed 29 matched mutant-wild-type and 16 matched SNP--wild-type protein systems. We found that the binding kinetics changes reflected by the changes of free energy changes induced by protein interaction mutations, which induce variations in the sensitive parameters of the bifurcation point, were a major cause of apoptosis pathway dysfunction, and mutations involved in sensitive interaction domains show high oncogenic potential. Our analysis provided a molecular basis for connecting protein mutations, protein interaction kinetics, network dynamics properties, and physiological function of a regulatory network. These insights provide a framework for coupling mutation genotype to tumorigenesis phenotype and help elucidate the logic of cancer initiation.
authors.affiliation: State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing 100871, China;
authors.forename: Linjie
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China;
authors.forename: Tanlin
authors.initials: T
authors.lastname: Sun
authors.affiliation: Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; jfpei@pku.edu.cn qi@pku.edu.cn.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Pei
authors.affiliation: State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing 100871, China; Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China jfpei@pku.edu.cn qi@pku.edu.cn.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ouyang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016000:Cluster Analysis; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism; D008962:Models, Theoretical; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins
keywords: dynamic bifurcation; mutation enrichment; mutation-induced oncogenesis; parameter sensitivity analysis; protein interaction kinetics