Molecular and hydrodynamic properties of human epidermal growth factor receptor HER2 extracellular domain and its homodimer: Experiments and multi-scale simulations

Vega, Juan Francisco; Ramos, Javier; Cruz, Víctor L.; Vicente-Alique, Ernesto; Sanchez-Sanchez, Eduardo; Sanchez-Fernandez, Adrian; Wang, Y.; Hu, Ping; Cortés, Javier; Martínez‐Salazar, Javier

doi:10.1016/j.bbagen.2017.06.012

Cited by 12 publications

(33 citation statements)

References 51 publications

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“…Interestingly, silencing endogenous copine-III did not significantly disrupt the in vitro tumor cell proliferation, invasion, or migration nor in vivo growth of MHCC97-H cells; furthermore, silencing copine-III did not induce the apoptosis of MHCC97-H cells. These may be due to the elevated expression of some types of receptor tyrosine kinases in HCC or other types of human cancer that compensates for the effects: a high level of EGFR has been identified in NSCLC28,29 and a high level of HER2 has been detected in some types of breast cancer 30,31. Clinical investigations showed that patients with advanced-stage HCC could not gain benefits from gefitinib (targeting EGFR) and trastuzumab (targeting ErbB2/HER2) 32–35.…”

Section: Discussionmentioning

confidence: 99%

Silencing the expression of copine-III enhances the sensitivity of hepatocellular carcinoma cells to the molecular targeted agent sorafenib

Chen

Jiang

Zhang

2018

CMAR

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BackgroundThe application of the oral targeted therapeutic agent sorafenib provides new hope for patients suffering from advanced stages of hepatocellular carcinoma (HCC), but the prognosis of such patients remains poor due to the rapid development of the multidrug resistance process in cancer pathogenesis. The present work evaluated whether copine-III, a novel cancer regulator encoded by the CPNE3 gene, would be a potential indicator of sorafenib resistance in HCC treatment.Materials and methodsThe endogenous expression of copine-III in clinical specimens was examined by quantitative polymerase chain reaction. Copine-III siRNA was transfected into HCC cells to downregulate copine-III expression. The effect of copine-III on sorafenib’s antitumor activation was identified by in vitro and in vivo experiments (MTT, Transwell, and flow cytometry as well as a nude mice model).ResultsHigh levels of copine-III in clinical specimens are related to poor prognosis of advanced HCC patients on sorafenib treatment. Infection of Ad-siCPNE3 significantly decreased the endogenous expression of copine-III and enhanced the susceptibility of MHCC97-H cells to sorafenib: the IC50 value decreased from 1.15±0.11 to 0.25±0.05 μmol/L. Moreover, silencing copine-III enhanced the effect of sorafenib on apoptosis, in vitro invasion/migration, and subcutaneous or intrahepatic growth of MHCC97-H cells in nude mice.ConclusionCopine-III is a novel potential indicator of prognosis for patients who received sorafenib for advanced HCC treatment.

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Section: Discussionmentioning

confidence: 99%

Silencing the expression of copine-III enhances the sensitivity of hepatocellular carcinoma cells to the molecular targeted agent sorafenib

Chen

Jiang

Zhang

2018

CMAR

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“…Both factors have been reported to play a role in the protein hydrodynamics. (35,41,42) In fact, our previous MD simulations performed on the members of the EGFR family in water, detected a large root mean square fluctuation concentrated in domains I, II and IV of the systems, indicating the existence of different movements of the domains and hence a high degree of flexibility (43)(44)(45) an increase of the molecular size of the complexes.…”

Section: Molecular Sizes and Hydrodynamic Properties 311 Sec Expermentioning

confidence: 91%

“…The TZM Herceptin © (stock solution at 21 mgml -1 ) was kindly provided by one Experimental details concerning size exclusion chromatography (SEC), dynamic light scattering (DLS) and electrophoretic mobility (EM) were reported in our previous articles (21,35). The sample concentration in both SEC and EM measurements were 1-3 mg·ml -1 .…”

Section: Methodsmentioning

confidence: 99%

“…Two systems that correspond to the interaction between one TZM molecule with either one or two g-eHER2 fragments (1:1 and 1:2 complexes), respectively, have been simulated. Both models were built taking into account the structures of the antibody and the g-eHER2-his reported in our previous work (35). The interaction between the TZM Fabs and the extracellular receptor fragments was assembled using as template the crystallographic structure (PDB code: 1N8Z) (9).…”

Section: Computational Simulations 221 Construction Of the Modelsmentioning

confidence: 99%

“…The ff12SB and Glycam-06 force fields were used for the protein and oligosaccharides, respectively(37). The simulation protocol used corresponds to the one described in our previous paper (35). It basically consisted in a series of minimizations and MD equilibration steps in the NPT and NVT ensembles to obtain a series of equilibrated initial conformations.…”

Section: Atomistic Molecular Dynamics (Md) Simulationsmentioning

confidence: 99%

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Hydrodynamic and electrophoretic properties of Trastuzumab/HER2 complexes. Experiments and modeling.

Ramos

Cruz

et al. 2018

Preprint

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The combination of hydrodynamic and electrophoretic experiments and computer simulations is indeed a powerful approach to study the interaction between proteins. In this work, we present hydrodynamic and electrophoretic experiments in aqueous solution along with molecular dynamics and hydrodynamic modeling to monitor and compute biophysical properties of the interactions between the extracellular domain of the HER2 protein (eHER2) and the monoclonal antibody trastuzumab (TZM). The importance of this system relies on the fact that the overexpression of HER2 protein is related with the poor prognosis breast cancers (HER2++ positives) being the TZM a monoclonal antibody for the treatment of this cancer. We have found and characterize two different complexes between the TZM and eHER2 proteins (1:1 and 1:2 TZM:eHER2 complexes). The conformational features of these complexes regulate their hydrodynamic and electrostatic properties. Thus, the results indicate a high degree of molecular flexibility in the systems, that ultimately leads to higher values of the intrinsic viscosity and as well as lower values of diffusion coefficient than those expected for simple globular proteins. A highly asymmetric charge distribution is detected for the monovalent complex (1:1 complex), which has strong implications in correlations between the experimental electrophoretic mobility and the modeled net charge. In order to understand the dynamics of these systems and the role of the specific domains involved, it is essential to find biophysical correlations between dynamics, macroscopic transport and electrostatic properties. The results should be of general interest for researchers working in this area.

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Crystallohydrodynamics of IgG

Ortega¹,

Cifre²,

Torre³

2018

Encyclopedia of Biophysics

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Molecular and hydrodynamic properties of human epidermal growth factor receptor HER2 extracellular domain and its homodimer: Experiments and multi-scale simulations

Cited by 12 publications

References 51 publications

Silencing the expression of copine-III enhances the sensitivity of hepatocellular carcinoma cells to the molecular targeted agent sorafenib

Silencing the expression of copine-III enhances the sensitivity of hepatocellular carcinoma cells to the molecular targeted agent sorafenib

Hydrodynamic and electrophoretic properties of Trastuzumab/HER2 complexes. Experiments and modeling.

Crystallohydrodynamics of IgG

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