The free energy landscape in translational science: How can somatic mutations result in constitutive oncogenic activation?

Chung Jung Tsai, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

The free energy landscape theory has transformed the field of protein folding. The significance of perceiving function in terms of conformational heterogeneity is gradually shifting the interest in the community from folding to function. From the free energy landscape standpoint the principles are unchanged: rather than considering the entire protein conformational landscape, the focus is on the ensemble around the bottom of the folding funnel. The protein can be viewed as populating one of two states: active or inactive. The basins of the two states are separated by a surmountable barrier, which allows the conformations to switch between the states. Unless the protein is a repressor, under physiological conditions it typically populates the inactive state. Ligand binding (or post-translational modification) triggers a switch to the active state. Constitutive allosteric mutations work by shifting the population from the inactive to the active state and keeping it there. This can happen by either destabilizing the inactive state, stabilizing the active state, or both. Identification of the mechanism through which they work is important since it may assist in drug discovery. Here we spotlight the usefulness of the free energy landscape in translational science, illustrating how oncogenic mutations can work in key proteins from the EGFR/Ras/Raf/Erk/Mek pathway, the main signaling pathway in cancer. Finally, we delineate the key components which are needed in order to trace the mechanism of allosteric events.

Original languageEnglish
Pages (from-to)6332-6341
Number of pages10
JournalPhysical Chemistry Chemical Physics
Volume16
Issue number14
DOIs
StatePublished - 14 Apr 2014

Funding

FundersFunder number
National Cancer Institute
National Institutes of HealthHHSN261200800001E
National Cancer InstituteZIABC010441

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