Activation loop

The polypeptide chain of Src tyrosine kinase, and related family members, comprises an N-terminal "unique" region, which directs membrane association and other as yet unknown functions, followed by a SH3 domain, a SH2 domain, and the two lobes of the protein kinase. Members of this family can be phosphorylated at two important tyrosine residues—one in the "activation loop" of the kinase domain (Tyr 419 in c-Src), the other in a short... 

C-terminal tail (Tyr 527 in c-Src). Phosphorylation of Tyr 419 activates the kinase phosphorylation of Tyr 527 inhibits it. Crystal structures of a fragment containing the last four domains of two members of this family were reported simultaneously in 1997—cellular Src by the group of Stephen Harrison and Hck by the group of John Kuriyan. The two structures are very similar, as expected since the 440 residue polypeptide chains have 60% sequence identity. The crucial C-proximal tyrosine that inhibits the activity of the kinases was phosphorylated in both cases the activation loop was not. 

It is worth emphasising too, that the position of those lines representing equilibria with the dissolved species, M, depend critically on the solubility of the ion, which is a continuous function of pH. For example, iron in moderately alkaline solution is expected to be very passive and so it is in borate solutions (in the absence of aggressive ions). However, the anodic polarization curve still shows a small active loop at low potential. 

Active Loop the region of an anodic polarisation curve of a metal comprising the active region and the active-passive transition. 

The a subunits, for which two isoforms exist in mammals (al, a2), contain conventional protein serine/threonine kinase domains at the N-terminus, with a threonine residue in the activation loop (Thr-172) that must be phosphorylated by upstream kinases (see below) before the kinase is active. The kinase domain is followed by an autoinhibitory domain, whose effect is somehow relieved by interaction with the other subunits. The C-terminal domain of the a subunit is required for the formation of a complex with the C-terminal domain of the (3 subunit, which in turn mediates binding to the y subunit. The al and a2 catalytic subunit isoforms are widely distributed, although a2 is most abundant in muscle and may be absent in cells of the endothelial/hemopoietic lineage. 

MAPK cascades are composed of three cytoplasmic kinases, the MAPKKK, MAPKK, and MAPK, that are regulated by phosphorylation (Fig. 1) [1, 2]. The MAPKKK, also called MEKK for MEK kinase, is a serine/threonine kinase. Selective activation of MAPKKKs by upstream cellular stimuli results in the phosphorylation of MAPKK, also called MEK for MAP/ERK kinase by the MAPKKK. MAPKKK members are structurally diverse and are differentially regulated by specific upstream stimuli. The MAPKK is phosphorylated by the MAPKKK on two specific serine/ threonine residues in its activation loop. The MAPKK family members are dual specificity kinases capable of phosphorylating critical threonine and tyrosine residues in the activation loop of the MAPKs. MAPKKs have the fewest members in the MAPK signaling module. MAPKs are a family of serine/threonine kinases that upon activation by their respective MAPKKs, are capable of phosphorylating cytoplasmic substrates as well as... 

All RTKs contain between one and three tyrosines in the kinase activation loop, which is composed of subdomains VII and VIII of the protein kinase catalytic core. Phosphorylation of these tyrosines has been shown to be critical for stimulation of catalytic activity and biological function for a number of RTKs, including insulin receptor, FGF receptor, VEGF receptor, PDGF receptor, Met (hepatocyte growth factor receptor), and TrkA (NGF receptor). A major exception is the EGF receptor, for which autophosphorylation of a conserved tyrosine in the activation loop does not seem to be involved in signaling. Substitution of tyrosine with phenylalanine has no effect on RTK activity or downstream signals. 

Insulin Inactive Catalytic domain Activation loop Tyr1162 in catalytic site... 

Insulin Active tris-Phosphorylated Release of activation loop by p l yr1162... 

Insulin-like growth factor I Active catalytic domain tris-Phosphorylated juxtamembrane region Activation loop released by pTyr1135... 

IGF-I) receptor IGF-I receptor Partially active catalytic domain bis-Phosphorylated catalytic Activation loop Tyr1135 disordered... 

The insulin-like growth factor I receptor is closely related to the insulin receptor. The RTK activity of the IGF-I receptor is regulated by intermolecular autophosphorylation at three sites within the activation loop. The crystal structure of the trisphosphorylated form of IGF-I RTK domain with an ATP analog and a specific peptide substrate showed that autophosphorylation stabilizes the activation loop in a conformation that facilitates catalysis. Furthermore, the structure revealed how... 

Another group solved the crystal structure of the IGF-I RTK domain phosphorylated at two tyrosine residues within the activation loop and bound to an ATP analog. The ligand is not in a conformation compatible with phosphoryl transfer, and the activation loop is partially disordered. IGF-I RTK is trapped in a half-closed, previously unobserved conformation. This conformation may be intermediary between the open, inactive conformation and closed, active conformation of insulin and IGF-I RTKs. 

Cheng Y, Zhang Y, McCammon JA (2006) How does activation loop phosphorylation modulate catalytic activity in the camp-dependent protein kinase a theoretical study. Protein Sci 15 672-683... 

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