Protein kinases Catalytic domain

The partial backbone assignment of the catalytic domain of protein kinase A (PKA) using a combination of NMR techniques was reported in 2004 [51]. This represented the first reported NMR assignment of any protein kinase catalytic domain. Backbone resonance assignment of the 42kDa protein was achieved using a combination of triple-labelled ( H, N)... 

The cytoplasmic domain primarily consists of the catalytic domain and various autophosphorylation sites that regulate catalytic function and serve as docking sites for SH2 do main-containing proteins. The protein kinase catalytic domains of RPTKs are highly conserved and similar in structure to those of the NRPTK (see above). 

FI/F2/F3, triad of RING-finger-like domains F, F-box domain USP, deubiquitinase catalytic domain OTU, a particular class of cystein protease domains RVP, retroviral protease domain DBA, ubiquitin-associated domain Pkinase, protein kinase catalytic domain. 

Selected entries from Methods in Enzymology [vol, page(s)] General Protein kinase classification, 200, 3 protein kinase catalytic domain sequence database identification of conserved features of primary structure and classification of family members,... 

Langer T, et al. NMR backbone assignment of a protein kinase catalytic domain by a combination of several approaches application to the catalytic subunit of cAMP-dependent protein kinase. ChemBioChem. 2004 5 1508-1516. 

Most native protein kinases are assembled in a modular fashion. This assembly always contains the protein kinase catalytic domain that catalyzes the transfer of a phosphate group to a substrate. Most kinases have additional variable domains that are involved in kinase recognition, activation, or localization. 

The ANP leceptoi exists in two forms, ANP and ANPg, both of which have been cloned. These membrane-bound guanylate cyclases have a single transmembrane domain, an intracellular protein kinase-like domain, and a catalytic cyclase domain, activation of which results in the accumulation of cychc guanosine monophosphate (cGMP). A third receptor subtype (ANP ) has been identified that does not have intrinsic guanylate cyclase activity and may play a role in the clearance of ANP. 

Hanks SK, Hunter T (1995) Protein kinases 6. The eukaryotic protein kinase superfamily kinase (catalytic) domain structure and classification. FASEB J 9 576-596... 

All related serine/threonine kinases and protein tyrosine kinases share a structurally conserved catalytic domain of about 270 amino acids. Numerous kinase catalytic domains have been structurally characterized by X-ray crystallography [14-18]. All of them share the highly conserved bilobal fold that is depicted in Fig. 15.2-1. In this fold, the N-terminal lobe is composed almost entirely of -sheets, whereas the C-terminal lobe is dominated by a-helices. The two lobes are joined by a polypeptide chain, which functions... 

Some receptors appear to be linked to the stimulation of guanylyl-cyclase. These membrane receptors mediate the action of the atrial natriuretic peptide (ANP), the heat-stable enterotoxin of E. coli and the receptors involved in fertilization in some species. These membrane receptors are glycoproteins of about 130-160 kDa spanning the membrane only once. The binding of the peptides occurs at the extracellular domain, while the intracellular regions contain both cyclase catalytic domains, converting GTP to cGMP, and a protein kinase-like domain. 

We have previously calculated conformational free energy differences for a well-suited model system, the catalytic subunit of cAMP-dependent protein kinase (cAPK), which is the best characterized member of the protein kinase family. It has been crystallized in three different conformations and our main focus was on how ligand binding shifts the equilibrium among these ([Helms and McCammon 1997]). As an example using state-of-the-art computational techniques, we summarize the main conclusions of this study and discuss a variety of methods that may be used to extend this study into the dynamic regime of protein domain motion. 

The catalytic subunit of cAPK contains two domains connected by a peptide linker. ATP binds in a deep cleft between the two domains. Presently, crystal structures showed cAPK in three different conformations, (1) in a closed conformation in the ternary complex with ATP or other tight-binding ligands and a peptide inhibitor PKI(5-24), (2) in an intermediate conformation in the binary complex with adenosine, and (3) in an open conformation in the binary complex of mammalian cAPK with PKI(5-24). Fig.l shows a superposition of the three protein kinase configurations to visualize the type of conformational movement. 

Tyrosine phosphorylated IRS interacts with and activates PI 3-kinase [3]. Binding takes place via the SRC homology 2 (SH2) domain of the PI 3-kinase regulatory subunit. The resulting complex consisting of INSR, IRS, and PI 3-kinase facilitates interaction of the activated PI 3-kinase catalytic subunit with the phospholipid substrates in the plasma membrane. Generation of PI 3-phosphates in the plasma membrane reemits phospholipid dependent kinases (PDKl and PDK2) which subsequently phosphorylate and activate the serine/threonine kinase Akt (synonym protein... 

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