Protein kinase family members

Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Stanton VP, Thirion JP, Hudson T, et al (1992) Molecular basis of myotonic dystrophy expansion of a trinucleotide (CTG) repeat at the 3 end of a transcript encoding a protein kinase family member. Cell... 

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. 

Protein kinase A (PKA) is a cyclic AMP-dependent protein kinase, a member of a family of protein kinases that are activated by binding of cAMP to their two regulatory subunits, which results in the release of two active catalytic subunits. Targets of PKA include L-type calcium channels (the relevant subunit and site of phosphorylation is still uncertain), phospholam-ban (the regulator of the sarcoplasmic calcium ATPase, SERCA) and key enzymes of glucose and lipid metabolism. 

Figure 3.5. Aminoglycoside kinases are members of the protein kinase family. Comparison of c-AMP-dependent protein kinase (cAPK) to APH(3 )-IIa and APH(3 )-IIIa. (A) cAPK (catalytic domain) from Mus musculus (pdb ID 2CPK). (B) APH(3 )-IIa from Klebsiella pneumoniae (pdb ID 1ND4). (C) APH(3 )-IIIa from Enterococcus faecalis (pdb ID 1L8T).

Kostich, M., English, J., Madison, V., et al. (2002) Human members of the eukaryotic protein kinase family. Genome Biol 3(9), 0043.1-0043.12. 

The protein kinase family encompasses more than three hundred members of critically important enzymes, each one with a specific role or function within the cell. These enzymes, ATP-phosphotransferases, recognize target proteins and through the phosphorylation of specific sites either activate or deactivate a particular pathway of signal transduction. Many of these signaling pathways are associated with cell surface receptors, which are located in the membranes that surround cells. The difference between the families of protein kinases is that they have different targets and generally fall into two major classes ... 

In the past several years there has been an explosion of structural studies within the protein kinase family [1-8]. These studies, initiated by the crystal structure of Protein Kinase A [9-12] (CAPK) have shown that all members of the protein kinase family fold into a uniform three-dimensional catalytic core. Yet this uniform three-dimensional fold exhibits both different surface charges and at least two major conformations. 

Vitale G, Bernardi L, Napolitani G et al (2000) Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J 352 739-745... 

Schneider AG, Mercereau-Puijalon O (2005) A new Apicomplexa-specific protein kinase family multiple members in Plasmodium falciparum, all with an export signature. BMC Genomics 6 30... 

Nunoue, K. Ohashi, K. Okano, I. Mizuno, K. LIMK-1 and LIMK-2, two members of a LIM motif-containing protein kinase family. Oncogene, 11, 701-710 (1995)... 

Callahan, C.A. Muralidhar, M.G. Lundgren, S.E. Scully, A.L. Thomas, J.B. Control of neuronal pathway selection by a Drosophila receptor protein-tyrosine kinase family member. Nature, 376, 171-174 (1995)... 

Son, M., Gundersen, R. E., and Nelson, D. L. (1993) A 2nd member of the novel Ca -dependent protein-kinase family from paramecium-tetraurelia—Purification and characterization. J. Biol. Chem. 268, 5940-5948. 

Comparison (or alignment) of amino acid sequences, also called homology search, often provides first-hand information on such conserved structural features and enables one to classify enzymes into families and predict the possible function of a new enzyme (86). A family of enzymes usually folds into similar 3-D structures, at least at the active site region. A typical example is the serine protease family whose members—trypsin, chymotrypsin, elastase, and subtilisin—commonly contain three active-site residues, Asp/His/Ser, which are known as the catalytic triad or charge relay system. Another example is the conserved features of catalytic domains of the highly diverse protein kinase family. In this kinase family, the ATP-binding (or phosphate-anchoring) sites present a consensus sequence motif of Gly-X-Gly-X-X-Gly (67,87). 

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... 

Figure 13.32 Regulation of the catalytic activity of members of the Src family of tyrosine kinases, (a) The inactive form based on structure determinations. Helix aC is in a position and orientation where the catalytically important Glu residue is facing away from the active site. The activation segment has a conformation that through steric contacts blocks the catalytically competent positioning of helix aC. (b) A hypothetical active conformation based on comparisons with the active forms of other similar protein kinases. The linker region is released from SH3, and the activation segment changes its structure to allow helix aC to move and bring the Glu residue into the active site in contact with an important Lys residue.

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