title: Effects of clinically relevant MPL mutations in the transmembrane domain revealed at the atomic level through computational modeling.
abstract: BACKGROUND
  Mutations in the thrombopoietin receptor (MPL) may activate relevant pathways and lead to chronic myeloproliferative neoplasms (MPNs). The mechanisms of MPL activation remain elusive because of a lack of experimental structures. Modern computational biology techniques were utilized to explore the mechanisms of MPL protein activation due to various mutations.
  
  
  RESULTS
  Transmembrane (TM) domain predictions, homology modeling, ab initio protein structure prediction, and molecular dynamics (MD) simulations were used to build structural dynamic models of wild-type and four clinically observed mutants of MPL. The simulation results suggest that S505 and W515 are important in keeping the TM domain in its correct position within the membrane. Mutations at either of these two positions cause movement of the TM domain, altering the conformation of the nearby intracellular domain in unexpected ways, and may cause the unwanted constitutive activation of MPL's kinase partner, JAK2.
  
  
  CONCLUSIONS
  Our findings represent the first full-scale molecular dynamics simulations of the wild-type and clinically observed mutants of the MPL protein, a critical element of the MPL-JAK2-STAT signaling pathway. In contrast to usual explanations for the activation mechanism that are based on the relative translational movement between rigid domains of MPL, our results suggest that mutations within the TM region could result in conformational changes including tilt and rotation (azimuthal) angles along the membrane axis. Such changes may significantly alter the conformation of the adjacent and intrinsically flexible intracellular domain. Hence, caution should be exercised when interpreting experimental evidence based on rigid models of cytokine receptors or similar systems.
authors.affiliation: BioMaPS Institute, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America. cancersimulation@gmail.com
authors.forename: Tai-Sung
authors.initials: TS
authors.lastname: Lee
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Wanlong
authors.initials: W
authors.lastname: Ma
authors.forename: Chen-Hsiung
authors.initials: CH
authors.lastname: Yeh
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
mesh_terms: D019943:Amino Acid Substitution; D019295:Computational Biology / Q000379:methods; D006801:Humans; D053614:Janus Kinase 2 / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D017434:Protein Structure, Tertiary; D053628:Receptors, Thrombopoietin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D050791:STAT Transcription Factors / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D053628:Receptors, Thrombopoietin; D050791:STAT Transcription Factors; C082218:MPL protein, human; D053614:Janus Kinase 2