title: Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.
abstract: The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase alphaC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling.
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Michael
authors.initials: M
authors.lastname: Kofler
authors.forename: Oliver
authors.initials: O
authors.lastname: Hantschel
authors.forename: Gerald D
authors.initials: GD
authors.lastname: Gish
authors.forename: Florian
authors.initials: F
authors.lastname: Grebien
authors.forename: Eidarus
authors.initials: E
authors.lastname: Salah
authors.forename: Philipp
authors.initials: P
authors.lastname: Neudecker
authors.forename: Lewis E
authors.initials: LE
authors.lastname: Kay
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry* / Q000378:metabolism; D051578:Proto-Oncogene Proteins c-fes / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; C496645:FES protein, human; D016315:Proto-Oncogene Proteins c-abl; D051578:Proto-Oncogene Proteins c-fes
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