Autoinhibition in Ras effectors Raf, PI3Kα, and RASSF5: a comprehensive review underscoring the challenges in pharmacological intervention

Biophysical Reviews - Tập 10 - Trang 1263-1282 - 2018
Ruth Nussinov1,2, Mingzhen Zhang1, Chung-Jung Tsai1, Tsung-Jen Liao1,3,4, David Fushman3,4, Hyunbum Jang1
1Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, USA
2Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
3Biophysics Program, Institute for Physical Science and Technology, University of Maryland, College Park, USA
4Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, USA

Tóm tắt

Autoinhibition is an effective mechanism that guards proteins against spurious activation. Despite its ubiquity, the distinct organizations of the autoinhibited states and their release mechanisms differ. Signaling is most responsive to the cell environment only if a small shift in the equilibrium is required to switch the system from an inactive (occluded) to an active (exposed) state. Ras signaling follows this paradigm. This underscores the challenge in pharmacological intervention to exploit and enhance autoinhibited states. Here, we review autoinhibition and release mechanisms at the membrane focusing on three representative Ras effectors, Raf protein kinase, PI3Kα lipid kinase, and NORE1A (RASSF5) tumor suppressor, and point to the ramifications to drug discovery. We further touch on Ras upstream and downstream signaling, Ras activation, and the Ras superfamily in this light, altogether providing a broad outlook of the principles and complexities of autoinhibition.

Tài liệu tham khảo

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