Protein kinase structure and function analysis with chemical tools

Shen, Kui; Hines, Anika L; Schwarzer, Dirk; Pickin, Kerry A.; Cole, Philip A.

doi:10.1016/j.bbapap.2005.08.020

Cited by 60 publications

(44 citation statements)

References 92 publications

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“…[305] Zur Lösung dieses Problems wurden Proteinsemisynthesen verwendet, um nichtspaltbare Mimetika von Phosphaten an den Modifizierungsstellen zu installieren (Schema 40 A). [306,307] Ein Zielprotein in dieser Beziehung ist die LMW-PTP (low molecular weight protein tyrosine phosphatase), die am PDGFr-vermittelten (platelet-derived growth factor receptor) Signaltransduktionsweg beteiligt ist. [308] Von der LMW-PTP ist bekannt, dass sie an zwei benachbarten Tyrosinresten phosphoryliert wird, die in unmittelbarer Nähe des aktiven Zentrums lokalisiert sind.…”

Section: Proteinphosphorylierungunclassified

Chemoselektive Ligations‐ und Modifikationsstrategien für Peptide und Proteine

2008

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Die Untersuchung biologischer Fragestellungen mit chemischen Methoden wird meist als “Chemische Biologie” bezeichnet und setzt voraus, dass biologisch relevante Makromoleküle, wie Peptide und Proteine, chemisch zugänglich sind. Auf der Festphasensynthese von Peptiden aufbauend wurden viele chemoselektive Ligations‐ und Modifikationstechniken zur Verknüpfung synthetischer Peptide oder funktionaler Einheiten zu größeren synthetischen, biologisch relevanten Makromolekülen entwickelt. Dieser Aufsatz fasst die aktuellen Entwicklungen auf dem Gebiet der chemoselektiven Ligations‐ und Modifikationsstrategien zusammen und illustriert ihre Anwendbarkeit an Beispielen aus der chemischen Totalsynthese von Proteinen bis hin zur Semisynthese natürlicher modifizierter Proteine.

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Section: Proteinphosphorylierungunclassified

Chemoselektive Ligations‐ und Modifikationsstrategien für Peptide und Proteine

2008

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“…Basin "2," at the MDM2 N-terminus, retains its location but is much diminished in prominence and extent, appearing more disconnected from the other basins. Basin "3" now dominates and appears better connected to basin "1," with a series of basins (1,3,5,6 Figure 3b; left) appearing to form a passage to/from peripheral regions, toward the bulk solution.…”

Section: Interaction Landscape Of Phosphorylated P53 With the Mdm2 Prmentioning

confidence: 99%

“…2 Protein kinases are the largest enzyme superfamily involved in cell signal transduction and therefore represent therapeutic targets for a wide range of diseases where signaling has become deregulated. 3 A major regulator of cellular signaling checkpoints, p53, is controlled by phosphorylation at various sites in stressed cells and its deregulation has been implicated in most cancers. [4][5][6] This stress originates in DNA damage, aberrant growth signals, interaction with chemotherapeutic drugs or protein-kinase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

et al. 2015

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T he interaction of p53 and MDM2 is modulated by the phosphorylation of p53. This mechanism is key to activating p53, yet its molecular determinants are not fully understood. To study the spatiotemporal characteristics of this molecular process we carried out Brownian dynamics simulations of the interactions of the MDM2 protein with a p53 peptide in its wild type state and when phosphorylated at Thr18 (pThr18) and Ser20 (pSer20). We found that p53 phosphorylation results in concerted changes in the topology of the interaction landscape in the diffusively bound encounter complex domain. These changes hinder phosphorylated p53 peptides from binding to MDM2 well before reaching the binding site. The underlying mechanism appears to involve shift of the peptide away from the vicinity of the MDM2 protein, peptide reorientation, and reduction in peptide residence time relative to wild-type p53 peptide. pThr18 and pSr20 p53 peptides experience reduction in residence times by factors of 13.6 and 37.5 respectively relative to the wild-type p53 peptide, indicating a greater role for Ser20 phosphorylation in abrogating p53 MDM2 interactions. These detailed insights into the effect of phosphorylation on molecular interactions are not available from conventional experimental and theoretical approaches and open up new avenues that incorporate molecular interaction dynamics, for stabilizing p53 against MDM2, which is a major focus of anticancer drug lead development.

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“…Caldesmon (CaD) is a protein that binds to Ca 2þ /calmodulin, Tm, actin, and myosin in cells (Liou et al, 2009). Two isoforms of CaD are produced from a single gene (Humphrey et al, 1992) through alternative splicing; these are the smooth muscle form h-CaD, with a high molecular weight of 130-140 kDa (Sobue Hunter, 2001;Shen et al, 2005;Annerén, 2008). Depending on whether they have the receptor-like features of ligand binding and transmembrane domains, TPKs are classified into receptor or non-receptor types.…”

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confidence: 99%

Effects of genistein on β‐catenin signaling and subcellular distribution of actin‐binding proteins in human umbilical CD105‐positive stromal cells

Shieh¹,

Li²,

Liao³

et al. 2010

Journal Cellular Physiology

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This study was performed to define the roles of actin-binding proteins in the regulation of actin filament assembly associated with cellular signal transduction pathways in stromal cell proliferation. Genistein, a tyrosine protein kinase inhibitor, decreased the intracellular Ca(2+) and attenuated cell proliferation and DNA synthesis through the beta-catenin and cyclin D1 pathway in human umbilical CD105-positive cells. Immunoprecipitation studies using anti-beta-actin antibody revealed that several actin-binding proteins implicated in cells include formin-2 (FMN-2), caldesmon (CaD), tropomyosin (Tm), and profilin. Protein levels of these proteins in whole cell lysates were not significantly changed by genistein. Three Tm isoforms, Tm-1, Tm-2, and Tm-4, were found to be present in cells. Genistein caused a reduction in levels of mRNAs coding for Tm-1 and Tm-4, but had no significant effect on Tm-2 mRNA levels. Immunofluorescence confocal scanning microscopy indicated that changes in the subcellular distribution of Tm and CaD, in which the diffuse cytosolic staining was shifted to show colocalization with actin stress fibers. In contrast, genistein-induced accumulation of FMN-2 and profilin in the peri-nuclear area. Silencing of FMN-2 by small interfering RNA resulted in increases of intracellular Ca(2+) and rendered genistein resistance in decreasing intracellular Ca(2+) in cells. These results provide the novel findings that genistein acts by modulating the cellular distribution of actin-binding proteins in association with alterations of cellular signal transduction pathways in human stromal cell proliferation.

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Protein kinase structure and function analysis with chemical tools

Cited by 60 publications

References 92 publications

Chemoselektive Ligations‐ und Modifikationsstrategien für Peptide und Proteine

Chemoselektive Ligations‐ und Modifikationsstrategien für Peptide und Proteine

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

Effects of genistein on β‐catenin signaling and subcellular distribution of actin‐binding proteins in human umbilical CD105‐positive stromal cells

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