title: Disrupting of E79 and K138 interaction is responsible for human muscle creatine kinase deficiency diseases.
abstract: Creatine kinase (CK) is a key enzyme for cellular energy metabolism, catalyzing the reversible phosphoryl transfer from phosphocreatine to ADP in vertebrates. Due to its important physiological functions, the acquired CK somatic mutations are closely correlated to diseases. In this study, the E79G point mutation was identified in two acute myocardial infarction patients with muscle CK activity deficiency. The crystal structure of CK indicates that the E79 and K138 interaction plays key roles in sustaining the recognition between N-terminal and C-terminal domains. Mutations of these residues caused pronounced loss of activity, conformational changes and distinct substrate synergism alteration. Moreover, spectroscopic spectra experiments suggested that mutations disrupting this hydrogen bond impaired the secondary and tertiary structure of CK. Meanwhile, protein folding experiments implied that mutations lead them to the partially unfolded state which made them easier to be inactivated and unfolded under environmental stresses. Furthermore, this partially unfolded state upon environmental stresses might gradually decrease the CK level in the patients. Thus, these results might provide clues in the mechanism of CK deficiency diseases.
authors.affiliation: Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, No. 99 West Huaihai Road, Xuzhou 221002, China.
authors.forename: Qing-Yun
authors.initials: QY
authors.lastname: Wu
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Hua-Yan
authors.initials: HY
authors.lastname: Guo
authors.forename: Jiang
authors.initials: J
authors.lastname: Cao
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Zeng
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Li
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Wang
authors.forename: Kai-Lin
authors.initials: KL
authors.lastname: Xu
mesh_terms: D002942:Circular Dichroism; D052283:Creatine Kinase, MM Form / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism*; D004795:Enzyme Stability; D006801:Humans; D007700:Kinetics; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013696:Temperature
chemical_list: D050505:Mutant Proteins; D011994:Recombinant Proteins; D052283:Creatine Kinase, MM Form