title: Intramolecular hydrophobic interactions are critical mediators of STAT5 dimerization.
abstract: STAT5 is an essential transcription factor in hematopoiesis, which is activated through tyrosine phosphorylation in response to cytokine stimulation. Constitutive activation of STAT5 is a hallmark of myeloid and lymphoblastic leukemia. Using homology modeling and molecular dynamics simulations, a model of the STAT5 phosphotyrosine-SH2 domain interface was generated providing first structural information on the activated STAT5 dimer including a sequence, for which no structural information is available for any of the STAT proteins. We identified a novel intramolecular interaction mediated through F706, adjacent to the phosphotyrosine motif, and a unique hydrophobic interface on the surface of the SH2 domain. Analysis of corresponding STAT5 mutants revealed that this interaction is dispensable for Epo receptor-mediated phosphorylation of STAT5 but essential for dimer formation and subsequent nuclear accumulation. Moreover, the herein presented model clarifies molecular mechanisms of recently discovered leukemic STAT5 mutants and will help to guide future drug development.
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Fahrenkamp
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.|College of Chemistry, Fuzhou University, Fuzhou, China.|Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich, Germany.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ernst
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Hildegard
authors.initials: H
authors.lastname: Schmitz-Van de Leur
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chatain
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Küster
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.affiliation: Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich, Germany.|Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.|Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, Jülich, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller-Newen
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D050799:STAT5 Transcription Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D018909:src Homology Domains
chemical_list: D050799:STAT5 Transcription Factor