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journal article·2017-10Open access

Piconewton‐Scale Analysis of Ras‐BRaf Signal Transduction with Single‐Molecule Force Spectroscopy

Chae‐Seok Lim, Cheng Wen, Yanghui Sheng, Guangfu Wang, Zhuan Zhou, Shiqiang Wang, Huaye Zhang, Anpei Ye, J. Julius Zhu

Small· Volume 13· Issue 40
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Abstract

Abstract Intermolecular interactions dominate the behavior of signal transduction in various physiological and pathological cell processes, yet assessing these interactions remains a challenging task. Here, this study reports a single‐molecule force spectroscopic method that enables functional delineation of two interaction sites (≈35 pN and ≈90 pN) between signaling effectors Ras and BRaf in the canonical mitogen‐activated protein kinase (MAPK) pathway. This analysis reveals mutations on BRaf at Q257 and A246, two sites frequently linked to cardio‐faciocutaneous syndrome, result in ≈10−30 pN alterations in RasBRaf intermolecular binding force. The magnitude of changes in RasBRaf binding force correlates with the size of alterations in protein affinity and in α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐sensitive glutamate receptor (‐R)‐mediated synaptic transmission in neurons expressing replacement BRaf mutants, and predicts the extent of learning impairments in animals expressing replacement BRaf mutants. These results establish single‐molecule force spectroscopy as an effective platform for evaluating the piconewton‐level interaction of signaling molecules and predicting the behavior outcome of signal transduction.
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Research context

OpenAlex topics: Force Microscopy Techniques and Applications · Molecular Junctions and Nanostructures · Cardiomyopathy and Myosin Studies

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Pharmacology University of Virginia School of Medicine Charlottesville VA 22908 USA

School of Electronic Engineering and Computer Science Peking University Beijing 100871 China

Undergraduate Class of 2011 Yuanpei Honors College Peking University Beijing 100871 China

Institute of Molecular Medicine Peking University Beijing 100871 China

School of Life Sciences Peking University Beijing 100871 China

Department of Microbiology and Center for Cell Signaling University of Virginia School of Medicine Charlottesville VA 22908 USA

Department of Neuroscience and Cell Biology Rutgers Robert Wood Johnson Medical School Piscataway NJ 08854 USA

Institute of Neuroscience Zhejiang University School of Medicine Hangzhou 310058 China

Donders Institute for Brain Cognition and Behaviour Radboud University 6525 EN Nijmegen Netherlands

Funding

National Research Foundation of Korea · National Natural Science Foundation of China · Ministry of Education of the People's Republic of China · National Institutes of Health

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