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Molecular modeling of nearly full-length ErbB2 receptor.

ABSTRACT: Members of the epidermal growth factor receptor family play important roles in various cellular processes, both in physiological and in pathological conditions. Dimerization and autophosphorylation of these receptor tyrosine kinases are key events of signal transduction. Details of the molecular events of the signaling are not entirely known. To facilitate the understanding of receptor structure and function at the molecular level, a molecular model was built for the nearly full-length ErbB2 dimer. Modeling was based on the x-ray or nuclear-magnetic resonance structures of extracellular, transmembrane, and intracellular domains. The extracellular domain was positioned above the cell membrane based on the distance determined from experimentally measured fluorescence resonance energy transfer. Favorable dimerization interactions are predicted for the extracellular, transmembrane, and protein kinase domains in the model of a nearly full-length dimer of ErbB2, which may act in a coordinated fashion in ErbB2 homodimerization, and also in heterodimers of ErbB2 with other members of the ErbB family.

SUBMITTER: Bagossi P

PROVIDER: S-EPMC1305137 | biostudies-literature | 2005 Feb

REPOSITORIES: biostudies-literature

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Molecular modeling of nearly full-length ErbB2 receptor.

Bagossi Péter P Horváth Gábor G Vereb György G Szöllösi János J Tözsér József J

Biophysical journal 20041213 2

Members of the epidermal growth factor receptor family play important roles in various cellular processes, both in physiological and in pathological conditions. Dimerization and autophosphorylation of these receptor tyrosine kinases are key events of signal transduction. Details of the molecular events of the signaling are not entirely known. To facilitate the understanding of receptor structure and function at the molecular level, a molecular model was built for the nearly full-length ErbB2 dim ...[more]

PMID: 15596490

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Project description:Hsp90 is a molecular chaperone essential for protein folding and activation in normal homeostasis and stress response. ATP binding and hydrolysis facilitate Hsp90 conformational changes required for client activation. Hsp90 plays an important role in disease states, particularly in cancer, where chaperoning of the mutated and overexpressed oncoproteins is important for function. Recent studies have illuminated mechanisms related to the chaperone function. However, an atomic resolution view of Hsp90 conformational dynamics, determined by the presence of different binding partners, is critical to define communication pathways between remote residues in different domains intimately affecting the chaperone cycle. Here, we present a computational analysis of signal propagation and long-range communication pathways in Hsp90. We carried out molecular dynamics simulations of the full-length Hsp90 dimer, combined with essential dynamics, correlation analysis, and a signal propagation model. All-atom MD simulations with timescales of 70 ns have been performed for complexes with the natural substrates ATP and ADP and for the unliganded dimer. We elucidate the mechanisms of signal propagation and determine "hot spots" involved in interdomain communication pathways from the nucleotide-binding site to the C-terminal domain interface. A comprehensive computational analysis of the Hsp90 communication pathways and dynamics at atomic resolution has revealed the role of the nucleotide in effecting conformational changes, elucidating the mechanisms of signal propagation. Functionally important residues and secondary structure elements emerge as effective mediators of communication between the nucleotide-binding site and the C-terminal interface. Furthermore, we show that specific interdomain signal propagation pathways may be activated as a function of the ligand. Our results support a "conformational selection model" of the Hsp90 mechanism, whereby the protein may exist in a dynamic equilibrium between different conformational states available on the energy landscape and binding of a specific partner can bias the equilibrium toward functionally relevant complexes.

Dataset Information

Molecular modeling of nearly full-length ErbB2 receptor.

Publications

Molecular modeling of nearly full-length ErbB2 receptor.

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