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1.
FIGURE 5.

FIGURE 5. From: Crystal Structure of the Src Family Kinase Hck SH3-SH2 Linker Regulatory Region Supports an SH3-dominant Activation Mechanism.

SH2 kinase linker interacts with the SH3 and kinase domains in near full-length Hck. Side chains of interacting residues of the SH2 kinase linker (orange), SH3 domain (gray), and kinase domain (pink) are shown as sticks, and hydrogen bonding is indicated by the black dashed lines (PDB code 1QCF).

John J. Alvarado, et al. J Biol Chem. 2010 November 12;285(46):35455-35461.
2.
FIGURE 2.

FIGURE 2. From: Crystal Structure of the Src Family Kinase Hck SH3-SH2 Linker Regulatory Region Supports an SH3-dominant Activation Mechanism.

Superposition of Src family kinase SH3 and SH2 domains. A, superposition of SH3 domains from Hck32L (red), Fyn32 (yellow; PDB code 1G83), Lck32 (blue; PDB code 1LCK), down-regulated near full-length Hck (cyan; PDB code 1QCF), and down-regulated near full-length c-Src (orange; PDB code 2SRC). B, superposition of the SH2 domains from the same structures in A. C, structure-based sequence alignment of SH3 and SH2 domains of Hck, c-Src, Fyn, and Lck (all residue numbers are based on the human c-Src crystal structure; PDB code 2SRC).

John J. Alvarado, et al. J Biol Chem. 2010 November 12;285(46):35455-35461.
3.
FIGURE 3.

FIGURE 3. From: Crystal Structure of the Src Family Kinase Hck SH3-SH2 Linker Regulatory Region Supports an SH3-dominant Activation Mechanism.

Comparison of Src family kinase SH3-SH2 domain architecture. A, interdomain contacts in Hck32L involve numerous salt bridges (denoted by black dashes) between residues Arg-139/Val-140 (depicted as balls-and-sticks) in the SH3 and Lys-151 in the SH2 domains. These residues have well defined conformations as shown by the 2FoFc electron density map (purple mesh), generated in Coot (20), and contoured at 1σ. B, comparisons of the tandem SH3-SH2 domain organizations in Hck32L (green), Fyn32 (yellow), and Lck32 (blue). C, comparison of the SH3-SH2 domain organization in Hck32L (green) to the down-regulated near full-length Hck (cyan) (PDB identifiers as indicated in Fig. 2).

John J. Alvarado, et al. J Biol Chem. 2010 November 12;285(46):35455-35461.
4.
FIGURE 1.

FIGURE 1. From: Crystal Structure of the Src Family Kinase Hck SH3-SH2 Linker Regulatory Region Supports an SH3-dominant Activation Mechanism.

X-ray crystal structure of the Hck regulatory region. A, domain organization of Src family kinases. See text for descriptions. B, crystal structure of near full-length, down-regulated Hck (PDB code 1QCF). Note that the SH3 domain (red) engages the SH2 kinase linker (orange), and the SH2 domain (blue) binds to the tyrosine-phosphorylated tail (cyan). Together, these interactions pack against the back of the kinase domain away from the active site to stabilize the inactive conformation. C, crystal structure of the Hck SH3-SH2-linker region (Hck32L). A and B were adapted from a review article by Engen et al. (2) for comparative purposes.

John J. Alvarado, et al. J Biol Chem. 2010 November 12;285(46):35455-35461.
5.
FIGURE 4.

FIGURE 4. From: Crystal Structure of the Src Family Kinase Hck SH3-SH2 Linker Regulatory Region Supports an SH3-dominant Activation Mechanism.

Conservation of SH2 contacts with the proximal end of the linker in Hck32L and near full-length Hck. A, extensive hydrogen bonding and salt bridges (both indicated by black dashed lines) between side chains stabilize the conformation of the linker adjacent to the SH2 domain in Hck32L. These interactions are evident from the well ordered and defined electron density maps, generated in Coot (20), with 2FoFc map coefficients, contoured at 1σ showing the SH2 domain residues (top, green mesh), linker residues (middle, magenta mesh), and both SH2 domain/linker residues (bottom, green/magenta mesh). B, interactions between the SH2 domain (blue) and SH2 kinase linker (orange) in Hck32L. C, interactions between the SH2 domain (light blue) and SH2 kinase linker (orange) within near full-length, down-regulated Hck (PDB code 1QCF).

John J. Alvarado, et al. J Biol Chem. 2010 November 12;285(46):35455-35461.
6.
FIGURE 6.

FIGURE 6. From: Crystal Structure of the Src Family Kinase Hck SH3-SH2 Linker Regulatory Region Supports an SH3-dominant Activation Mechanism.

Activation of Hck but not c-Src by an SH3-binding peptide. A, comparison of the Hck32L crystal structure (this study) and the corresponding SH3-SH2 linker region from an active c-Src structure (PDB code 1Y57). In the c-Src structure, the SH3-SH2 linker region is uncoupled from the kinase domain (see text for details). The SH3 domain is rendered in red; the SH3-SH2 connector in gray; the SH2 domain in blue, and the linker in orange. Note that the linker remains bound to the SH3 domain in the c-Src structure but is disordered and therefore not observed in the Hck32L structure with the exception of SH2 contacts. B, Src-YEEI and Hck-YEEI are active in vitro. Recombinant purified Src-YEEI and Hck-YEEI were titrated into the Z'-LyteTM assay as shown. Each reaction was monitored in triplicate, and data are expressed as percent of peptide phosphorylation relative to a control phosphopeptide ± S.D. C, SH3-binding peptide VSL12 activates Hck-YEEI but not Src-YEEI. In vitro kinase assays were performed using equivalent amounts of Src-YEEI and Hck-YEEI that gave ∼20–25% maximal activity in the absence of the VSL12 peptide. Reactions were run in the presence of increasing kinase: VSL12 peptide ratios as shown. Each reaction was monitored in triplicate, and data are expressed as percent of peptide phosphorylation relative to a control phosphopeptide ± S.D.

John J. Alvarado, et al. J Biol Chem. 2010 November 12;285(46):35455-35461.

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