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Structure and Regulation of Src Family Kinases Oncogene (2004) 23, 7918–7927 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc Structure and regulation of Src family kinases Titus J Boggon1,2 and Michael J Eck*,1,2 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA; 2Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA Src family kinases are prototypical modular signaling (Koegl et al., 1994; Resh, 1999). The SH4 region is proteins. Their conserved domain organization includes a followed by a ‘unique’ domain of 50–70 residues, which myristoylated N-terminal segment followed by SH3, SH2, is divergent among family members. and tyrosine kinase domains, and a short C-terminal tail. A hallmark of Src kinases is a short C-terminal tail, Structural dissection of Src kinases has elucidated the which bears an autoinhibitory phosphorylation site canonical mechanisms of phosphotyrosine recognition by (Tyrosine 527 in Src) (Cooper et al., 1986). Like most the SH2domain and proline-motif recognition by the SH3 protein kinases, Src family members require phosphor- domain. Crystallographic analysis of nearly intact Src ylation within a segment of the kinase domain termed kinases in the autoinhibited state has shown that these the activation loop for full catalytic activity.In Src, this protein interaction motifs turn inward and lock the kinase autophosphorylation site is Tyrosine 416 (for consis- in an inactive conformation via intramolecular interac- tency, we use chicken Src numbering throughout) tions. The autoinhibited Src kinase structures reveal a (Smart et al., 1981). In vivo, Src kinases are phosphory- mode of domain assembly used by other tyrosine kinases lated on either Tyr 416 (in their active state) or Tyr 527 outside the Src family, including Abl and likely Tec family (in the inactive state).The inactivating phosphorylation kinases. Furthermore, they illustrate the underlying on Tyr 527 is carried out by the Src-specific kinase Csk regulatory principles that have proven to be general (Nada et al., 1991) or its homolog Chk (Hamaguchi among diverse modular signaling proteins. Although there et al., 1996; Davidson et al., 1997). Phosphorylation of is considerable structural information available for the the C-terminal tail promotes assembly of the SH2, SH3, autoinhibited conformation of Src kinases, how they may and kinase domains into an autoinhibited conformation assemble into active signaling complexes with substrates maintained by intimate interactions among these and regulators remains largely unexplored. domains (Sicheri et al., 1997; Williams et al., 1997; Oncogene (2004) 23, 7918–7927. doi:10.1038/sj.onc.1208081 Xu et al., 1997). The discovery of the SH2 domain as a functionally Keywords: Src regulation; modular signaling; CD4/CD8a important, but noncatalytic segment of B100 residues conserved in v-Fps, Abl, and Src kinases (Sadowski et al., 1986) gave rise to the concept of ‘modular signaling domain’ (Pawson, 1995).Studies of the function and specificity of the SH2 and SH3 domains The domain structure of Src kinases of Src and of their effect on the activity of the adjacent kinase domain have provided a powerful paradigm for Src family nonreceptor tyrosine kinases are present in the functional dissection of a host of modular signaling essentially all metazoan cells, where their regulated domains (see Pawson (2004) for an excellent review and activation by diverse growth factor, cytokine, adhesion, historical perspective).Likewise, structural dissection of and antigen receptors is critical for generating an Src kinases into their component domains and eventual appropriate cellular response to external stimuli (Brown elucidation of the structure of the essentially intact Src and Cooper, 1996; Thomas and Brugge, 1997).The nine kinases have provided a paradigm for structural analysis members of the Src family include Src, Lck, Hck, Fyn, of many multidomain signaling proteins.In the follow- Blk, Lyn, Fgr, Yes, and Yrk.Src kinases share a ing paragraphs, we briefly describe the structure of the conserved domain structure consisting of consecutive isolated domains of Src kinases.In later sections, SH3, SH2, and tyrosine kinase (SH1) domains we consider in more detail the structure of autoinhibited (Figure 1).All family members also contain an SH4 Src kinases and the implications of the structure for Src membrane-targeting region at their N-terminus, which is function and regulation. always myristoylated and sometimes palmitoylated The SH2 domain *Correspondence: MJ Eck, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, MA, USA; The architecture of the SH2 domain and the structural E-mail: [email protected] basis for its recognition of phosphorylated tyrosine was Structure and regulation of Src kinases TJ Boggon and MJ Eck 7919 Figure 1 The domain structure of Src family kinases.The Src kinase architecture consists of four domains: the unique region, which varies among family members, followed by the SH3, SH2, and tyrosine kinase domains.The approximate extent of each domain is indicated, with the unique, SH3, SH2, and kinase domains colored dark blue, salmon, light green, and light blue, respectively, here and throughout the review.The activation loop of the kinase domain is colored red, and the activating (Tyr 416) and autoinhibitory (Tyr 527) phosphorylation sites are indicated.Conserved residue Arg 175 in the SH2 domain is critical for phosphotyrosine recognition; Trp 260 at the extreme N-terminus of the kinase domain is important for autoinhibition (see text).In the autoinhibited form of Src kinases, the SH2 domain binds the phosphorylated C-terminal tail, and the SH3 domain binds the linker segment between the SH2 and kinase domain, which forms a polyproline type II helix (see Figure 3).By convention, amino-acid residues are numbered as in chicken Src.In the lower panel, Protein Data Bank (PDB) accession codes for selected Src family structures are given, and the approximate region included in each three-dimensional structure is indicated.PDB accession codes correspond to: Lck unique domain in complex with the CD4 (1Q68) and CD8a (1Q69) cytoplasmic tails (Kim et al., 2003); 1SHG, crystal structure of aspectrin SH3 domain (Musacchio et al., 1992); 1SHF, the Fyn SH3 domain (Noble et al., 1993); 1SRM, the NMR structure of Src SH3 domain (Yu et al., 1992); 1SHA, 1SPR, and 1LCJ, crystal structures of SH2 domains of Src and Lck, respectively (1SHA and 1LCJ are in complex with tyrosine- phosphorylated peptides) (Waksman et al., 1992, 1993; Eck et al., 1993); 1LCK and 1G83, crystal structures of SH2–SH3 fragments of Lck (Eck et al., 1994) and Fyn (Arold et al., 2001); 3LCK, Lck kinase domain in its active conformation, phosphorylated on the activation loop tyrosine (Yamaguchi and Hendrickson, 1996); 2SRC (Xu et al., 1999), 1FMK (Xu et al., 1997), 2HCK (Sicheri et al., 1997), Src and Hck crystal structures incorporating SH2-SH3-Kinase domains in the autoinhibited conformation first revealed in near-simultaneous studies of the domains derived from Abl (Overduin et al., 1992), the p85 subunit of PI 3-OH kinase (Booker et al., 1992), and of Src itself (Waksman et al., 1992). The now-familiar fold consists of a central b-sheet, with a single helix packed against each side.These elements of secondary structure and the loops that connect them form two recognition pockets, one that coordinates phosphotyr- osine, and the second on the opposite side of the central sheet that typically binds one or more hydrophobic residues just C-terminal to the phosphotyrosine (Eck et al., 1993; Waksman et al., 1993). The phosphotyrosyl recognition pocket is rather highly conserved among SH2 domains, and contains a universally conserved arginine residue (Arg 175 in Src) that forms requisite electrostatic interactions with the phosphorylated tyrosine (Waksman et al., 1992). Not surprisingly, the Figure 2 The Lck SH2 domain bound to a high-affinity C-terminal recognition pocket is much more divergent, phosphopeptide.The Lck SH2 domain binds the pYEEI -motif accounting for the differences among SH2 domains in phosphopeptide in a two-pronged manner.The phosphorylated recognition of specific phosphotyrosine-bearing se- tyrosine and the isoleucine at the pY þ 3 position insert into well- defined recognition pockets on the surface of the domain.The quences (Kuriyan and Cowburn, 1997).Historically, intervening glutamic acid residues extend across the surface of the phosphopeptide library-binding studies of SH2 specifi- domain.The Lck SH2 domain is shown as a solvent-accessible city established a paradigm for such studies of modular surface represented by white dots, the peptide is shown as a CPK signaling domains, and revealed distinct classes of model.Figure adapted from Eck et al.(1993) specificity for the three to five residues following the phosphorylated tyrosine (Songyang et al., 1993). Src- family SH2 domains bind preferentially to the pY-E-E-I The common-fold and phosphotyrosyl-binding prop- motif, coordinating the phosphotyrosine and isoleucine erties of the SH2 domain belie its versatility as a residues in the canonical recognition pockets (Figure 2). protein–protein recognition module.SH2 domains have Polar and electrostatic interactions favor glutamic acid evolved to function in diverse multidomain proteins, residues at the pY þ 1 and þ 2 positions, but many including transcription
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