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Signaling receptors often encounter multiple ligands and have been shown to respond selectively to generate appropriate, context-specific outcomes. At thermal equilibrium, ligand specificity is limited by the relative affinities of ligands for their receptors. Here, we present a non-equilibrium model in which receptors overcome thermodynamic constraints to preferentially signal from specific ligands while suppressing others. In our model, multi-site phosphorylation and active receptor degradation act in concert to regulate ligand specificity, with receptor degradation, a common motif in eukaryotes, providing a previously under-appreciated layer of control. Here, ligand-bound receptors undergo sequential phosphorylation, with progression restarted by ligand unbinding or receptor turnover. High-affinity complexes are kinetically sorted toward degradation-prone states, while low-affinity complexes are sorted toward inactivated states, both limiting signaling. As a result, network activity is maximized for ligands with intermediate affinities. This mechanism explains paradoxical experimental observations in receptor tyrosine kinase signaling, including non-monotonic dependence of signaling output on ligand affinity and kinase activity. Given the ubiquity of multi-site phosphorylation and ligand-induced degradation across signaling receptors, we propose that kinetic sorting may be a general non-equilibrium ligand-discrimination strategy used by multiple signaling receptors.
Pubmed ID: 41160435
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The Wellcome Trust is the largest charity in the UK. We fund innovative biomedical research, in the UK and internationally, spending over 600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust is an independent charity funding research to improve human and animal health. Established in 1936 and with an endowment of around 13 billion, it is the UK's largest non-governmental source of funds for biomedical research. What we do We spend over 600 million every year both in the UK and internationally achieving our mission. Funding We support many different kinds of research and activities with the ultimate aim of protecting and improving human and animal health. This support is not restricted to UK researchers - we devote significant funding to international research too. Biomedical science Our biomedical science funding enables the investigation of health and disease in humans and animals. This includes funding for scientists, clinicians and veterinarians at different career stages. Technology transfer Our technology transfer funding supports the development of innovative, early-stage projects with potential medical applications. Medical humanities Our medical humanities funding supports research into biomedical ethics and the history of medicine. Public engagement Our public engagement funding promotes interest, excitement and debate around science and society. Capital funding Our capital funding is for large-scale construction or refurbishment projects in the UK that support science, public engagement, medical history, or the activities of learned societies. Strategic awards Our Strategic Awards provide flexible funding that adds value to excellent research groups. Managing a grant This area contains information and resources to help you manage a grant once it has been awarded, from the grant-start certificate to the end-of-grant report and beyond. Education Resources Teaching and education Resources to help promote contemporary science in the curriculum and to enable young people to engage with biomedical science. Tree of Life Darwin200 Big Picture Science Learning Centres Scientific animations Creative Encounters Courses and conferences Trust-run conferences, courses and workshops for scientists, historians, ethicists, social scientists, teachers, healthcare professionals and policymakers, held in the UK and overseas. Advanced Courses Scientific conferences Conference centres Retreats History of medicine Biomedical ethics Biomedical resources Tools, databases and information to support different areas of biomedical research, including genomics, post-genomics and developmental biology. Animal research Genomics Model organisms Microorganisms Post-genomics Tissues Researcher support Support and advice for all kinds of engagement activities to help you communicate your work in the most effective and rewarding way possible. About researcher support National opportunities Regional opportunities Highlights Publications Browse a wealth of publications covering all aspects of the work we fund. Wellcome Trust websites Explore a range of sites covering key biomedical topics and our public engagement activities.
View all literature mentionsNIGMS supports basic biomedical research that is not targeted to specific diseases. NIGMS funds studies on genes, proteins, and cells, as well as on fundamental processes like communication within and between cells, how our bodies use energy, and how we respond to medicines. The results of this research increase our understanding of life and lay the foundation for advances in disease diagnosis, treatment, and prevention. NIGMS also supports research training programs that produce the next generation of biomedical scientists, and it has special programs to encourage underrepresented minorities to pursue biomedical research careers. The National Institute of General Medical Sciences (NIGMS) primarily supports research that lays the foundation for advances in disease diagnosis, treatment, and prevention. The Institute's research training programs help provide the next generation of scientists. Each year, NIGMS-supported scientists make many advances in understanding fundamental life processes. In the course of answering basic research questions, these investigators increase our knowledge about the mechanisms and pathways involved in certain diseases. Institute grantees also develop important new tools and techniques, some of which have medical applications. In recognition of the significance of their work, a number of NIGMS grantees have received the Nobel Prize and other high scientific honors. At any given time, NIGMS supports approximately 4,700 research grants—approximately 11 percent of the grants funded by NIH as a whole. NIGMS also supports approximately 26 percent of the trainees who receive assistance from NIH. NIGMS also supports approximately 25% of the trainees who receive assistance from NIH. The Institute places great emphasis on supporting investigator-initiated research grants. It funds a limited number of research center grants in selected fields, including structural genomics, trauma and burn research, and systems biology. In addition, NIGMS supports several important scientific resources, including the NIGMS Human Genetic Cell Repository and the Protein Data Bank.
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