A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases.

@article{Pirruccello2006, abstract = {The p21-activated kinases (PAKs) are serine/threonine kinases that are involved in a wide variety of cellular functions including cytoskeletal motility, apoptosis, and cell cycle regulation. PAKs are inactivated by blockage of the active site of the kinase domain by an N-terminal regulatory domain. GTP-bound forms of Cdc42 and Rac bind to the regulatory domain and displace it, thereby allowing phosphorylation of the kinase domain and maximal activation. A key step in the activation process is the phosphorylation of the activation loop of one PAK kinase domain by another, but little is known about the underlying recognition events that make this phosphorylation specific. We show that the phosphorylated kinase domain of PAK2 dimerizes in solution and that this association is prevented by addition of a substrate peptide. We have identified a crystallographic dimer in a previously determined crystal structure of activated PAK1 in which two kinase domains are arranged face to face and interact through a surface on the large lobe of the kinase domain that is exposed upon release of the auto-inhibitory domain. The crystallographic dimer is suggestive of an engagement that mediates trans-autophosphorylation. Mutations at the predicted dimerization interface block dimerization and reduce the rate of autophosphorylation, supporting the role of this interface in PAK activation.}, author = {Pirruccello, Michelle and Sondermann, Holger and Pelton, Jeffrey G. and Pellicena, Patricia and Hoelz, Andr\'{e} and Chernoff, Jonathan and Wemmer, David E. and Kuriyan, John }, citeulike-article-id = {2054452}, doi = {10.1016/j.jmb.2006.06.017}, journal = {J Mol Biol}, keywords = {activation, amino-acid, article-predikin, binding, catalysis, catalytic, conformation, crystallography, data, dimerization, domain, enzyme, folding, homology, human, kinase, kinetics, models, molecular, mutation, p21-activated, phosphopeptides, phosphorylation, protein, protein-serine-threonine, sequence, sites, structure, tertiary, x-ray}, month = {Aug}, number = {2}, pages = {312--326}, posted-at = {2007-12-04 03:22:14}, priority = {2}, title = {A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases.}, url = {http://dx.doi.org/10.1016/j.jmb.2006.06.017}, volume = {361}, year = {2006} }

TY - JOUR ID - Pirruccello2006 L3 - citeulike-article-id:2054452 TI - A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases. JF - J Mol Biol VL - 361 IS - 2 SP - 312 EP - 326 N2 - The p21-activated kinases (PAKs) are serine/threonine kinases that are involved in a wide variety of cellular functions including cytoskeletal motility, apoptosis, and cell cycle regulation. PAKs are inactivated by blockage of the active site of the kinase domain by an N-terminal regulatory domain. GTP-bound forms of Cdc42 and Rac bind to the regulatory domain and displace it, thereby allowing phosphorylation of the kinase domain and maximal activation. A key step in the activation process is the phosphorylation of the activation loop of one PAK kinase domain by another, but little is known about the underlying recognition events that make this phosphorylation specific. We show that the phosphorylated kinase domain of PAK2 dimerizes in solution and that this association is prevented by addition of a substrate peptide. We have identified a crystallographic dimer in a previously determined crystal structure of activated PAK1 in which two kinase domains are arranged face to face and interact through a surface on the large lobe of the kinase domain that is exposed upon release of the auto-inhibitory domain. The crystallographic dimer is suggestive of an engagement that mediates trans-autophosphorylation. Mutations at the predicted dimerization interface block dimerization and reduce the rate of autophosphorylation, supporting the role of this interface in PAK activation. KW - activation KW - amino-acid KW - article-predikin KW - binding KW - catalysis KW - catalytic KW - conformation KW - crystallography KW - data KW - dimerization KW - domain KW - enzyme KW - folding KW - homology KW - human KW - kinase KW - kinetics KW - models KW - molecular KW - mutation KW - p21-activated KW - phosphopeptides KW - phosphorylation KW - protein KW - protein-serine-threonine KW - sequence KW - sites KW - structure KW - tertiary KW - x-ray AU - Pirruccello, Michelle AU - Sondermann, Holger AU - Pelton, Jeffrey AU - Pellicena, Patricia AU - Hoelz, André AU - Chernoff, Jonathan AU - Wemmer, David AU - Kuriyan, John PY - 2006/Aug// UR - http://dx.doi.org/10.1016/j.jmb.2006.06.017 ER -