Protein kinases control a wide range of cellular functions by phosphorylating a tyrosine or Serine/Threonine residue of another protein. They play important roles in gene ex
Fig. 1 The basic catalytic cycle for substrate phosphorylation by a protein tyrosine kinase.
Src family protein tyrosine kinases
The Src family protein tyrosine kinases (SFKs) has been the subject of extensive studies for decades since it was first discovered from the study of Rous sarcoma virus. While there are already numerous excellent reviews available elsewhere on the discovery, structure, function, activity, mechanism, pathways and dynamic regulation of Src family tyrosine kinase, for the sake of completeness here we only provide a brief introduction to the most essential facts that are related to the thesis work. Major focus is placed on the human c-Src protein, which serves as the prototype for this 11-member multi-kinase family (Blk, Brk, Fgr, Frk, Fyn, Hck, Lck, Lyn, Src, Srm, Yes).
Like other types of protein tyrosine kinases, when activated in the cell Src family tyrosine kinases catalyze the following phosphorylation reactions by transferring the terminal γ-phosphate from ATP to a tyrosine side chain in the presence of magnesium ion (Fig. 1):
MgATP− + protein(tyrosine)-OH→ protein(tyrosine)-OPO32− + MgADP + H+
All 11 members of Src family kinases have the same structural organization of multidomains, as shown in Fig 1 for c-Src. From N-terminus to C-terminus, c-Src contains a short myristoyl group, a unique domain, an SH3 domain, an SH2 domain, an SH2-kinase linker region, a kinase domain (aka SH1 domain) and a C-terminal regulatory tail.
X-ray crystallographic studies of the Src tyrosine kinase show that the inactive and active forms of c-Src exhibit dramatically different conformations. The X-ray structure of c-Src in the inactive form, reveals how the modular SH2 and SH3 domain cooperate in the auto-inhibitory interactions regulating the activity of the kinase catalytic domain: SH2 domain binds to the C-terminal tail and SH3 domain binds to the SH2-kinase linker such that all three domains are engaged in an inter-locked “assembled” form. A recently solved crystal structure of c-Src in a disassembled form provides a glimpse into the active conformations of c-Src, although it is perhaps only one of the many possible active conformations c-Src can take: the SH3 and SH2 domains are found to rest in the upper east region to the kinase domain, with only the SH3 domain and SH2-kinase linker making contact with the kinase N-terminal lobe. Compared with their position in the assemble inactive form, the SH3 and SH2 domains are rotated approximately 130° relative to the kinase domain.