title: The effects of R683S (G) genetic mutations on the JAK2 activity, structure and stability.
abstract: Janus kinase 2 (JAK2) is an important mediator of cytokine receptor signaling and plays key roles in the hematopoietic and immune response. The acquired JAK2 R683S (G) mutations are presumed to be a biomarker for B-cell acute lymphoblastic leukemia (B-ALL). However, how these mutations leading to the B-ALL is still unclear. The crystal structure of JAK2 JH2 domain suggests that the residue R683 locating in the linker between the N and C lobes of JH2 domain is important for keeping the compact structure, activity and structural stability of this domain. Mutations R683S, R683G and R683E significantly increase JAK2 activity and decrease its structural stability. While the R683K and R683H mutations almost have no effects on the JAK2 activity and structural stability. Furthermore, the spectroscopic experiments imply that mutations R683S, R683G and R683E impair the structure of JAK2 JH2 domain, and lead JAK2 to partially unfolded state. It may be this partially unfolded state that caused JAK2 R683S (G) constitutive activation. This study provides clues in understanding the mechanism of JAK2 R683S (G) mutations caused B-ALL.
authors.affiliation: Department of Biology, Xuzhou Medical College, No. 99 West Huaihai Road, Xuzhou, 221002, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Hua-Yan
authors.initials: HY
authors.lastname: Guo
authors.forename: Man
authors.initials: M
authors.lastname: Wang
authors.forename: Hong-Li
authors.initials: HL
authors.lastname: Geng
authors.forename: Mei-Ru
authors.initials: MR
authors.lastname: Bian
authors.forename: Jiang
authors.initials: J
authors.lastname: Cao
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Zeng
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Wang
authors.forename: Qing-Yun
authors.initials: QY
authors.lastname: Wu
mesh_terms: D019943:Amino Acid Substitution; D004789:Enzyme Activation; D004795:Enzyme Stability; D006801:Humans; D053614:Janus Kinase 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D007698:Kinesis; D008958:Models, Molecular; D009154:Mutation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D053614:Janus Kinase 2
keywords: 1-anilino-8-naphthalenesulfonic acid; ALL; ANS; Acute lymphoblastic leukemia; B-ALL; B-cell acute lymphoblastic leukemia; Emax; JAK; JAK homology; JH; Janus Kinase; Janus kinase 2; MPDs; Myeloproliferative disorders; STAT5; Signal transducer and activator of transcription 5; Structural stability; The emission maximum of the intrinsic fluorescence; WT; Wild type