A "Tug of War" Maintains a Dynamic Protein-Membrane Complex: Molecular Dynamics Simulations of C-Raf RBD-CRD Bound to K-Ras4B at an Anionic Membrane.

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Abstract

Association of Raf kinase with activated Ras triggers downstream signaling cascades toward regulating transcription in the cells' nucleus. Dysregulation of Ras-Raf signaling stimulates cancers. We investigate the C-Raf RBD and CRD regions when bound to oncogenic K-Ras4B at the membrane. All-atom molecular dynamics simulations suggest that the membrane plays an integral role in regulating the configurational ensemble of the complex. Remarkably, the complex samples a few states dynamically, reflecting a competition between C-Raf CRD- and K-Ras4B- membrane interactions. This competition arises because the interaction between the RBD and K-Ras is strong while the linker between the RBD and CRD is short. Such a mechanism maintains a modest binding for the overall complex at the membrane and is expected to facilitate fast signaling processes. Competition of protein-membrane contacts is likely a common mechanism for other multiprotein complexes, if not multidomain proteins at membranes.

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RAS Proteins and Their Regulators in Human Disease.

Dhirendra Simanshu, Dwight Nissley, Frank McCormick (2017)

RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS' interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.

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Mikhail A. Lomize, Andrei L. Lomize, Irina Pogozheva … (2006)

The Orientations of Proteins in Membranes (OPM) database provides a collection of transmembrane, monotopic and peripheral proteins from the Protein Data Bank whose spatial arrangements in the lipid bilayer have been calculated theoretically and compared with experimental data. The database allows analysis, sorting and searching of membrane proteins based on their structural classification, species, destination membrane, numbers of transmembrane segments and subunits, numbers of secondary structures and the calculated hydrophobic thickness or tilt angle with respect to the bilayer normal. All coordinate files with the calculated membrane boundaries are available for downloading. http://opm.phar.umich.edu.

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Ilia G Denisov, Stephen Sligar (2016)

Membrane proteins have long presented a challenge to biochemical and functional studies. In the absence of a bilayer environment, individual proteins and critical macromolecular complexes may be insoluble and may display altered or absent activities. Nanodisc technology provides important advantages for the isolation, purification, structural resolution and functional characterization of membrane proteins. In addition, the ability to precisely control the nanodisc composition provides a nanoscale membrane surface for investigating molecular recognition events.