Protein kinase constitutively active catalytic domain

Binding of phosphotyrosine 527 to the SH2 domain induces conformational strains in the SH3 and kinase domains, distorting the kinase active site so it is catalytically inactive. The kinase activity of cellular Src proteins is normally activated by removing the phosphate on tyrosine 527. (b) Domain structure of c-Src and v-Sre. Phosphorylation of tyrosine 527 by Csk, another cellular tyrosine kinase, inactivates the Src kinase activity. The transforming v-Src oncoprotein encoded by Rous sarcoma virus is missing the C-terminal 18 amino acids including tyrosine 527 and thus is constitutively active. [Part (a) from F. Sicheri et al.,... 

Pseudokinases are a protein family that constitute approximately 10% of the human kinome (for reviews on this topic, see Ref. 51-53). These proteins are characterized by the presence of a kinase-homology domain predicted to lack enzymatic activity due to the absence of at least one of the three conserved critical catalytic motifs (1) the Val-Ala-Ile-Lys (VAIK) motif in subdomain II, in which the side-chain of Lys interacts with the a and p phosphates of ATP (2) the His-Arg-Asp (HRD) motif in subdomain Ylb, in which the aspartic acid is the catalytic residue and (3) the Asp-Phe-Gly (DFG) motif in sub-domain VII, in which the carboxylic moiety of aspartic acid binds the Mg11 ion that coordinates the p and y phosphates of ATP. Owing to their lack of intrinsic phosphoryl-transfer catalytic activity, pseudokinase domain-containing... 

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