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Review
. 2009 Dec;19(6):643-9.
doi: 10.1016/j.sbi.2009.10.001. Epub 2009 Nov 18.

SH2 domains: modulators of nonreceptor tyrosine kinase activity

Panagis Filippakopoulos  1 , Susanne Müller, Stefan Knapp
Affiliations
Review

SH2 domains: modulators of nonreceptor tyrosine kinase activity

Panagis Filippakopoulos et al. Curr Opin Struct Biol. 2009 Dec.

Abstract

The Src homology 2 (SH2) domain is a sequence-specific phosphotyrosine-binding module present in many signaling molecules. In cytoplasmic tyrosine kinases, the SH2 domain is located N-terminally to the catalytic kinase domain (SH1) where it mediates cellular localization, substrate recruitment, and regulation of kinase activity. Initially, structural studies established a role of the SH2 domain stabilizing the inactive state of Src family members. However, biochemical characterization showed that the presence of the SH2 domain is frequently required for catalytic activity, suggesting a crucial function stabilizing the active state of many nonreceptor tyrosine kinases. Recently, the structure of the SH2-kinase domain of Fes revealed that the SH2 domain stabilizes the active kinase conformation by direct interactions with the regulatory helix alphaC. Stabilizing interactions between the SH2 and the kinase domains have also been observed in the structures of active Csk and Abl. Interestingly, mutations in the SH2 domain found in human disease can be explained by SH2 domain destabilization or incorrect positioning of the SH2. Here we summarize our understanding of mechanisms that lead to tyrosine kinase activation by direct interactions mediated by the SH2 domain and discuss how mutations in the SH2 domain trigger kinase inactivation.

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Figures

Figure 1
Figure 1
Phylogenetic tree based on SH2 domain sequence and domain organization in nonreceptor tyrosine kinases. The different types of domain architectures shown in the lower panel are highlighted by different colors and in the phylogenetic tree the name of kinases with a certain domain organization are colored accordingly. The SH2–kinase unit is indicated by a dashed line. In Jak kinases this unit involves probably both kinase domains, which seem to form a compact structural unit [34].
Figure 2
Figure 2
Interfaces between kinase domains and SH2/linker. (a) SH2–kinase domain arrangement in Fes. Shown is the orientation of the domains in low-resolution surface representation in the left panel. Structural details upon inactivation are shown in the middle panel and a detailed view of the SH2–αC interaction is shown in the right panel. Key residues of the interaction are highlighted. (b) Domain organization in active Csk. (c) Domain organization in inactive Zap70. (d) Domain packing in inactive Abl (left panel), active Abl (middle panel), and detailed view of the interaction between the SH2 domain and the kinase domain (right panel). As indicated in the lower panel in all surface representations SH3 domains are shown in orange, SH2 domains in blue, linker regions between SH2 and kinase domain in yellow, helix αC in red, activation segments in purple and the kinase domains are shown in beige.
Figure 3
Figure 3
Location of mutations identified in human disease projected onto the structure of the Btk SH2 domain. Data used in the figure were taken from Ref. [45•]. Mutations that destabilize the SH2 domain are shown in yellow and those affecting pTyr binding are highlighted in blue. The locations of the destabilizing mutation R335W in Itk, P80Q in Zap70, and W460C in Fer are also shown. The major structural elements harboring mutations as well as the C-termini and N-termini are labeled.
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References

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