The Conformational Plasticity of Protein Kinases

Huse, Morgan; Kuriyan, John

doi:10.1016/s0092-8674(02)00741-9

Cited by 1,601 publications

(1,622 citation statements)

References 48 publications

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“…This brings about phosphorylation of the cytoplasmic Eph (as well as B-class ephrin) domains and downstream signaling initiation [3]. Kinase activation is controlled by the phosphorylation of residues in the activation loop and the juxtamembrane segment, which affect the inter-lobe(subdomain) dynamics of the kinase domain [31][32][33][34][35]. The minimal ligand-binding domain of the receptor is in blue and the ephrin receptor-binding domain is in pink.…”

Section: Discussionmentioning

confidence: 99%

“…Ligand binding brings together two or more catalytically repressed kinase domains and holds them in an orientation favoring phosphorylation in trans. Stimulation of the kinase activity nearly always involves the phosphorylation of the kinase activation loop, which in its non-phosphorylated form blocks the active site [31]. In some RTKs, including the Eph, Kit, Flt, platelet-derived growth-factor beta (PDGFβ) and TrkB receptors, the juxtamembrane region is also involved in regulation of the kinase activity [31,32].…”

Section: Activation Of the Eph Kinase Domainmentioning

confidence: 99%

“…Stimulation of the kinase activity nearly always involves the phosphorylation of the kinase activation loop, which in its non-phosphorylated form blocks the active site [31]. In some RTKs, including the Eph, Kit, Flt, platelet-derived growth-factor beta (PDGFβ) and TrkB receptors, the juxtamembrane region is also involved in regulation of the kinase activity [31,32]. The crystal structure of the intracellular region of EphB2 [33] revealed that the unphosphorylated juxtamembrane region forms a well-ordered structure interacting with the N-terminal lobe of the kinase, presumably causing the distortion of a key α-helix and leading to kinase inactivation.…”

Section: Activation Of the Eph Kinase Domainmentioning

confidence: 99%

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Cell–cell signaling via Eph receptors and ephrins

Himanen

Saha

Nikolov

2007

Current Opinion in Cell Biology

227

202

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SummaryEph receptors are the largest subfamily of receptor tyrosine kinases regulating cell shape, movements and attachment. The interactions of the Ephs with their ephrin ligands are restricted to the sites of cell-cell contact since both molecules are membrane attached. This review summarizes recent advances in our understanding of the molecular mechanisms underlining the diverse functions of the molecules during development and in the adult organism. The unique properties of this signaling system that are of highest interest and have been the focus of intense investigations are as follows: (i) the signal is often simultaneously transduced in both ligand-and receptor-expressing cells, (ii) signaling via the same molecules can generate opposing cellular reactions depending on the context, and (iii) the Ephs and the ephrins are divided in two subclasses with promiscuous intra-subclass interactions, but rarely observed inter-subclass interactions.

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Section: Discussionmentioning

confidence: 99%

Section: Activation Of the Eph Kinase Domainmentioning

confidence: 99%

Section: Activation Of the Eph Kinase Domainmentioning

confidence: 99%

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Cell–cell signaling via Eph receptors and ephrins

Himanen

Saha

Nikolov

2007

Current Opinion in Cell Biology

227

202

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“…The non-phosphorylated activation loop on the bi-lobed kinase domain prevents the substrate from access to the catalytic center, whereas the phosphorylation of the loop perturbs the conformation so that the substrate makes an easy access. Modified from Huse and Kuriyan [21].…”

Section: Site-directed Mutagenesis Of Ser-71 Ser-128 Thr-168 and Thmentioning

confidence: 99%

Self-activation of Serine/Threonine Kinase AfsK on Autophosphorylation at Threonine-168

et al. 2006

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A Hanks-type protein kinase AfsK autophosphorylates on threonine residue(s) and phosphorylates AfsR, a global regulator for secondary metabolism in Streptomyces coelicolor A3(2). Mass spectrometry of a tryptic digest of the autophosphorylated form of AfsKD C corresponding to the kinase catalytic domain (Met-1 to Arg-311) of AfsK, together with subsequent site-directed mutagenesis of the candidate amino acids, identified threonine-168 as a single autophosphorylation site. Threonine-168 is located in the activation loop that is known for some Ser/Thr kinases to modulate kinase activity on phosphorylation of one or more threonine residues within the loop. Consistent with this, mutant T168D, in which Thr-168 was replaced by Asp, became a constitutively active kinase; it phosphorylated AfsR to the same extent as AfsKD C produced in and purified from Escherichia coli cells during which a considerable population of it had been already phosphorylated intermolecularly. All these findings show that autophosphorylation or intermolecular phosphorylation of threonine-168 in AfsK accounts for the self-activation of its kinase activity.Keywords serine/threonine kinase, autophosphorylation, self-activation, antibiotic production, Streptomyces A number of proteins in Streptomyces, including Streptomyces coelicolor A3(2), are phosphorylated on their serine/threonine and tyrosine residues in response to developmental phases [1,2]. Recent completion of the genome projects of S. coelicolor A3(2) [3] and S. avermitilis [4] has revealed the presence of about 40 proteins having a kinase catalytic domain similar to those of the typical eukaryotic serine/threonine and tyrosine kinases. All these observations clearly show that a given Streptomyces strain possesses several protein kinases of eukaryotic type, some of which regulate growth, morphological development and secondary metabolism. Of the protein serine/threonine kinases in Streptomyces, AfsK that phosphorylates serine/threonine residues of AfsR was first discovered, representing the first instance in the bacterial world in which the ability of a bacterial Hankstype protein kinase to phosphorylate an exogenous protein has been demonstrated [5]. The AfsK-AfsR system in S. coelicolor A3(2) globally controls the biosynthesis of secondary metabolites including actinorhodin, undecylprodigiosin, methylenomycin, and a calciumdependent antibiotic [2].Autophosphorylated amino acid residues of Hanks kinases in prokaryotes, such as PrkC in Bacillus subtilis [6], PknB in Mycobacterium tuberculosis [7ϳ9], PknD, PknE and PknF in M. tuberculosis [9], and PknH in M.

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“…[15][16][17] Truncations or mutations that disrupt the autoinhibitory interactions often result in a constitutively active functional form wherein no activity control is possible, leading to aberrant function. 18,19 Autoinhibition is increasingly seen in proteins involved in a diverse set of biological phenomena. [15][16][17][20][21][22][23] Mechanisms that are known to relieve autoinhibition include posttranslational modification, proteolysis, and addition of proteins or small ligands.…”

Section: Introductionmentioning

confidence: 99%

NMR reveals novel mechanisms of protein activity regulation

Kalodimos

2011

Protein Science

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NMR spectroscopy is one of the most powerful tools for the characterization of biomolecular systems. A unique aspect of NMR is its capacity to provide an integrated insight into both the structure and intrinsic dynamics of biomolecules. In addition, NMR can provide siteresolved information about the conformation entropy of binding, as well as about energetically excited conformational states. Recent advances have enabled the application of NMR for the characterization of supramolecular systems. A summary of mechanisms underpinning protein activity regulation revealed by the application of NMR spectroscopy in a number of biological systems studied in the lab is provided.

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The Conformational Plasticity of Protein Kinases

Cited by 1,601 publications

References 48 publications

Cell–cell signaling via Eph receptors and ephrins

Cell–cell signaling via Eph receptors and ephrins

Self-activation of Serine/Threonine Kinase AfsK on Autophosphorylation at Threonine-168

NMR reveals novel mechanisms of protein activity regulation

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