scholarly journals An allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Massimiliano Anselmi ◽  
Jochen S. Hub
Keyword(s):  
Tyrosine Phosphatase ◽  
Binding Mode ◽  
Sh2 Domain ◽  
Activation Mechanism ◽  
Ligand Affinity ◽  
Allosteric Interaction ◽  
Ligand Stimulation ◽  
Novel Strategy ◽  
Multiple Signaling ◽  
Insight Into

Abstract SHP2 is a protein tyrosine phosphatase (PTP) involved in multiple signaling pathways. Mutations of SHP2 can result in Noonan syndrome or pediatric malignancies. Inhibition of wild-type SHP2 represents a novel strategy against several cancers. SHP2 is activated by binding of a phosphopeptide to the N-SH2 domain of SHP2, thereby favoring dissociation of the N-SH2 domain and exposing the active site on the PTP domain. The conformational transitions controlling ligand affinity and PTP dissociation remain poorly understood. Using molecular simulations, we revealed an allosteric interaction restraining the N-SH2 domain into a SHP2-activating and a stabilizing state. Only ligands selecting for the activating N-SH2 conformation, depending on ligand sequence and binding mode, are effective activators. We validate the model of SHP2 activation by rationalizing modified basal activity and responsiveness to ligand stimulation of several N-SH2 variants. This study provides mechanistic insight into SHP2 activation and may open routes for SHP2 regulation.

scholarly journals An allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase

2020 ◽  
Author(s):  
Massimiliano Anselmi ◽  
Jochen S. Hub
Keyword(s):  
Tyrosine Phosphatase ◽  
Binding Mode ◽  
Sh2 Domain ◽  
Activation Mechanism ◽  
Ligand Affinity ◽  
Allosteric Interaction ◽  
Ligand Stimulation ◽  
Novel Strategy ◽  
Multiple Signaling ◽  
Insight Into

ABSTRACTSHP2 is a protein tyrosine phosphatase (PTP) involved in multiple signaling pathways. Mutations of SHP2 can result in Noonan syndrome or pediatric malignancies. Inhibition of wild-type SHP2 represents a novel strategy against several cancers. SHP2 is activated by binding of a phosphopeptide to the N-SH2 domain of SHP2, thereby favoring dissociation of the N-SH2 domain and exposing the active site on the PTP domain. The conformational transitions controlling ligand affinity and PTP dissociation remain poorly understood. Using molecular simulations, we revealed an allosteric interaction restraining the N-SH2 domain into a SHP2-activating and a stabilizing state. Only ligands selecting for the activating N-SH2 conformation, depending on ligand sequence and binding mode, are effective activators. We validate the model of SHP2 activation by rationalizing modified basal activity and responsiveness to ligand stimulation of several N-SH2 variants. This study provides mechanistic insight into SHP2 activation and may open routes for SHP2 regulation.

scholarly journals Mechanistic insight into a peptide hormone signaling complex mediating floral organ abscission

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Julia Santiago ◽  
Benjamin Brandt ◽  
Mari Wildhagen ◽  
Ulrich Hohmann ◽  
Ludwig A Hothorn ◽  
...  
Keyword(s):  
Hormone Receptors ◽  
Peptide Hormone ◽  
Binding Pocket ◽  
Binding Mode ◽  
Floral Organ ◽  
Activation Mechanism ◽  
Signaling Complex ◽  
Floral Abscission ◽  
Peptide Hormone Receptors ◽  
Insight Into

Plants constantly renew during their life cycle and thus require to shed senescent and damaged organs. Floral abscission is controlled by the leucine-rich repeat receptor kinase (LRR-RK) HAESA and the peptide hormone IDA. It is unknown how expression of IDA in the abscission zone leads to HAESA activation. Here we show that IDA is sensed directly by the HAESA ectodomain. Crystal structures of HAESA in complex with IDA reveal a hormone binding pocket that accommodates an active dodecamer peptide. A central hydroxyproline residue anchors IDA to the receptor. The HAESA co-receptor SERK1, a positive regulator of the floral abscission pathway, allows for high-affinity sensing of the peptide hormone by binding to an Arg-His-Asn motif in IDA. This sequence pattern is conserved among diverse plant peptides, suggesting that plant peptide hormone receptors may share a common ligand binding mode and activation mechanism.

scholarly journals SHP2 Mediates the Localized Activation of Fyn Downstream of the α6β4 Integrin To Promote Carcinoma Invasion

2010 ◽  
Vol 30 (22) ◽  
pp. 5306-5317 ◽  
Author(s):  
Xiaoqing Yang ◽  
Udayan Dutta ◽  
Leslie M. Shaw
Keyword(s):  
Tyrosine Phosphatase ◽  
Specific Interaction ◽  
Sh2 Domain ◽  
Human Breast ◽  
Mechanistic Insight ◽  
C Terminus ◽  
Α6β4 Integrin ◽  
Aggressive Tumor ◽  
Tumor Types ◽  
Insight Into

ABSTRACT Src family kinase (SFK) activity is elevated in many cancers, and this activity correlates with aggressive tumor behavior. The α6β4 integrin, which is also associated with a poor prognosis in many tumor types, can stimulate SFK activation; however, the mechanism by which it does so is not known. In the current study, we provide novel mechanistic insight into how the α6β4 integrin selectively activates the Src family member Fyn in response to receptor engagement. Both catalytic and noncatalytic functions of SHP2 are required for Fyn activation by α6β4. Specifically, the tyrosine phosphatase SHP2 is recruited to α6β4 and its catalytic activity is stimulated through a specific interaction of its N-terminal SH2 domain with pY1494 in the β4 subunit. Fyn is recruited to the α6β4/SHP2 complex through an interaction with phospho-Y580 in the C terminus of SHP2. In addition to activating Fyn, this interaction with Y580-SHP2 localizes Fyn to sites of receptor engagement, which is required for α6β4-dependent invasion. Of significance for tumor progression, phosphorylation of Y580-SHP2 and SFK activation are increased in orthotopic human breast tumors that express α6β4 and activation of this pathway is dependent upon Y1494.

scholarly journals Crystal Structure of the Streptomyces coelicolor Sortase E1 Transpeptidase Provides Insight into the Binding Mode of the Novel Class E Sorting Signal

PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0167763 ◽  
Author(s):  
Michele D. Kattke ◽  
Albert H. Chan ◽  
Andrew Duong ◽  
Danielle L. Sexton ◽  
Michael R. Sawaya ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Streptomyces Coelicolor ◽  
Binding Mode ◽  
The Novel ◽  
Sorting Signal ◽  
Insight Into ◽  
Class E

scholarly journals Characterization of the Kaposi's Sarcoma-Associated Herpesvirus K1 Signalosome

2005 ◽  
Vol 79 (19) ◽  
pp. 12173-12184 ◽  
Author(s):  
Bok-Soo Lee ◽  
Sun-Hwa Lee ◽  
Pinghui Feng ◽  
Heesoon Chang ◽  
Nam-Hyuk Cho ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Inflammatory Cytokines ◽  
Kaposi's Sarcoma ◽  
Mutational Analysis ◽  
Tyrosine Phosphatase ◽  
Kaposi’S Sarcoma ◽  
Sh2 Domain ◽  
Signaling Proteins ◽  
Cellular Signal ◽  
Cellular Components

ABSTRACT Kaposi's sarcoma (KS) is a multifocal angiogenic tumor and appears to be a hyperplastic disorder caused, in part, by local production of inflammatory cytokines. The K1 lymphocyte receptor-like protein of KS-associated herpesvirus (KSHV) efficiently transduces extracellular signals to elicit cellular activation events through its cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). To further delineate K1-mediated signal transduction, we purified K1 signaling complexes and identified its cellular components. Upon stimulation, the K1 ITAM was efficiently tyrosine phosphorylated and subsequently interacted with cellular Src homology 2 (SH2)-containing signaling proteins Lyn, Syk, p85, PLCγ2, RasGAP, Vav, SH2 domain-containing protein tyrosine phosphatase 1/2, and Grab2 through its phosphorylated tyrosine residues. Mutational analysis demonstrated that each tyrosine residue of K1 ITAM contributed to the interactions with cellular signaling proteins in distinctive ways. Consequently, these interactions led to the marked augmentation of cellular signal transduction activity, evidenced by the increase of cellular tyrosine phosphorylation and intracellular calcium mobilization, the activation of NF-AT and AP-1 transcription factor activities, and the production of inflammatory cytokines. These results demonstrate that KSHV K1 effectively recruits a set of cellular SH2-containing signaling molecules to form the K1 signalosome, which elicits downstream signal transduction and induces inflammatory cytokine production.

scholarly journals 3D micro-environment regulates NF–κβ dependent adhesion to induce monocyte differentiation

2018 ◽  
Author(s):  
Anindita Bhattacharya ◽  
Mahesh Agarwal ◽  
Rachita Mukherjee ◽  
Prosenjit Sen ◽  
Deepak Kumar Sinha
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
The Novel ◽  
Monocyte Adhesion ◽  
Cellular Functions ◽  
Monocyte Differentiation ◽  
Summary Statement ◽  
Necessary And Sufficient ◽  
Multiple Signaling ◽  
Insight Into

AbstractDifferentiation of monocytes entails their relocation from blood to the tissue, hence accompanied by an altered physicochemical micro-environment. While the mechanism by which the biochemical make-up of the micro-environment induces differentiation is known, the fluid-like to gel-like transition in the physical micro-environment is not well understood. Monocytes maintain non-adherent state to prevent differentiation. We establish that irrespective of the chemical makeup, a 3D gel-like micro-environment induces a positive-feedback loop of adhesion-MAPK-NF-κβ activation to facilitate differentiation. In 2D fluid-like micro-environment, adhesion alone is capable of inducing differentiation via the same positive-feedback signalling. Chemical inducer treatment in fluid-like micro-environment, increases the propensity of monocyte adhesion via a brief pulse of p-MAPK. The adhesion subsequently elicit differentiation, establishing that adhesion is both necessary and sufficient to induce differentiation in 2D/3D micro-environment. Our findings challenge the notion that adhesion is a result of monocyte differentiation. Rather it’s the adhesion which triggers the differentiation of monocytes. MAPK, and NF-κβ being key molecules of multiple signaling pathways, we hypothesize that biochemically inert 3D gel-like micro-environment would also influence other cellular functions.Summary statementThis article brings out a new insight into the novel mechanisms of monocyte differentiation solely driven by physical micro-environment and adhesion.

scholarly journals Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist

2020 ◽  
Author(s):  
Polina Isaikina ◽  
Ching-Ju Tsai ◽  
Nikolaus Dietz ◽  
Filip Pamula ◽  
Anne Grahl ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Binding Mode ◽  
Activation Mechanism ◽  
Structural Basis ◽  
Cc Chemokine ◽  
Gi Protein ◽  
Agonist And Antagonist ◽  
Cc Chemokine Receptor 5 ◽  
Chemokine Receptor 5

AbstractThe human CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) that plays a major role in inflammation and is involved in the pathology of cancer, HIV, and COVID-19. Despite its significance as a drug target, the activation mechanism of CCR5, i.e. how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric Gi protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N-terminus of agonist chemokines pushes onto an aromatic connector that transmits activation to the canonical GPCR microswitch network. This activation mechanism differs significantly from other CC chemokine receptors that bind shorter chemokines in a shallow binding mode and have unique sequence signatures and a specialized activation mechanism.One-sentence summaryThe structure of CCR5 in complex with the chemokine agonist [6P4]CCL5 and the heterotrimeric Gi protein reveals its activation mechanism

scholarly journals A strategy to suppress STAT1 signalling conserved in pathogenic poxviruses and paramyxoviruses

2021 ◽  
Author(s):  
Callum Talbot-Cooper ◽  
Teodors Pantelejevs ◽  
John P. Shannon ◽  
Christian R. Cherry ◽  
Marcus T. Au ◽  
...  
Keyword(s):  
Sequence Similarity ◽  
Nipah Virus ◽  
Sh2 Domain ◽  
Binding Motif ◽  
Virus Infections ◽  
Stat Proteins ◽  
Interferon Stimulated Genes ◽  
Independent Mode ◽  
Insight Into ◽  
Diverse Virus

The induction of interferon-stimulated genes by signal transducer and activator of transcription (STAT) proteins, is a critical host defence to fight virus infections. Here, a highly expressed poxvirus protein 018 is shown to inhibit IFN-induced signalling by binding the SH2 domain of STAT1 to prevent STAT1 association with an activated IFN receptor. Despite the presence of additional inhibitors of IFN-induced signalling, a poxvirus lacking 018 was attenuated in mice. The 2.0-angstrom crystal structure of the 018:STAT1 complex reveals a mechanism for a high-affinity, pTyr-independent mode of binding to an SH2 domain. Furthermore, the STAT1 binding motif of 018 shows sequence similarity to the STAT1-binding proteins from Nipah virus, which like 018, block the association of STAT1 with an IFN receptor. Taken together, these results provide detailed mechanistic insight into a potent mode of STAT1 antagonism, found to exist in genetically diverse virus families.

scholarly journals Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S

2019 ◽  
Vol 10 (46) ◽  
pp. 10789-10801 ◽  
Author(s):  
Jonas Lategahn ◽  
Marina Keul ◽  
Philip Klövekorn ◽  
Hannah L. Tumbrink ◽  
Janina Niggenaber ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Binding Mode ◽  
Drug Resistant ◽  
X Ray ◽  
Covalent Inhibitors ◽  
Epidermal Growth ◽  
Resistant Mutants ◽  
Insight Into ◽  
Egfr T790m

We present inhibitors of drug resistant mutants of EGFR including T790M and C797S. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR to gain insight into their binding mode.

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