Thresholds and ultrasensitivity from negative cooperativity

The secrets of making signaling responsive Many receptor proteins that respond to biological signals form multimeric complexes, which gives them more sophisticated regulatory properties than those of simple one-to-one binding reactions. Ha et al. describe how the binding of multiple ligands to receptor complexes can generate threshold effects and switch-like ultrasensitivity. If binding of the first ligand makes binding of a second less likely (a property known as negative cooperativity), and binding can also deplete the total amount of ligand present, the way the system responds to various doses of the ligand can change dramatically from a very gradual one to a switch-like behavior. The authors provide theory and experiments that explain how such systems function and may be suited to biological regulation. Science, this issue p. 990 How binding of multiple ligands to receptors shapes dose responses. Negative cooperativity is a phenomenon in which the binding of one or more molecules of a ligand to a multimeric receptor makes it more difficult for subsequent ligand molecules to bind. Negative cooperativity can make a multimeric receptor’s response more graded than it would otherwise be. However, through theory and experimental results, we show that if the ligand binds the receptor with high affinity and can be appreciably depleted by receptor binding, then negative cooperativity produces a qualitatively different type of response: a highly ultrasensitive response with a pronounced threshold. Because ultrasensitivity and thresholds are important for generating various complex systems-level behaviors, including bistability and oscillations, negative cooperativity may be an important ingredient in many types of biological responses.

[1]  M E Greenberg,et al.  A cytoplasmic inhibitor of the JNK signal transduction pathway. , 1997, Science.

[2]  G. Rubin,et al.  Identification of Constitutive and Ras-Inducible Phosphorylation Sites of KSR: Implications for 14-3-3 Binding, Mitogen-Activated Protein Kinase Binding, and KSR Overexpression , 1999, Molecular and Cellular Biology.

[3]  R. Prywes,et al.  In vitro squelching of activated transcription by serum response factor: evidence for a common coactivator used by multiple transcriptional activators. , 1992, Nucleic acids research.

[4]  V. Rivera,et al.  Transcriptional squelching re-examined , 1997, Nature.

[5]  Jehoshua Bruck,et al.  Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[6]  K.,et al.  KSR stimulates Raf-1 activity in a kinase-independent manner. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. Koshland,et al.  Amplification and adaptation in regulatory and sensory systems. , 1982, Science.

[8]  James E Ferrell,et al.  The Prozone Effect Accounts for the Paradoxical Function of the Cdk-Binding Protein Suc1/Cks. , 2016, Cell reports.

[9]  L. Pauling,et al.  The Oxygen Equilibrium of Hemoglobin and Its Structural Interpretation. , 1935, Proceedings of the National Academy of Sciences of the United States of America.

[10]  D. Koshland,et al.  An amplified sensitivity arising from covalent modification in biological systems. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Jean‐Paul Herman,et al.  LUEGO: a cost and time saving gel shift procedure. , 2011, BioTechniques.

[12]  D. Koshland,et al.  Comparison of experimental binding data and theoretical models in proteins containing subunits. , 1966, Biochemistry.

[13]  D. Bray,et al.  Computer-based analysis of the binding steps in protein complex formation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J. Ferrell,et al.  Ultrasensitivity part III: cascades, bistable switches, and oscillators. , 2014, Trends in biochemical sciences.

[15]  E. Kool,et al.  Hydrogen bonding, base stacking, and steric effects in dna replication. , 2001, Annual review of biophysics and biomolecular structure.

[16]  D E Koshland,et al.  Negative cooperativity in regulatory enzymes. , 1969, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Nicolas E. Buchler,et al.  Molecular titration and ultrasensitivity in regulatory networks. , 2008, Journal of molecular biology.

[18]  A. Nordheim,et al.  Regulatory squelching , 1994, FEBS letters.

[19]  J. Ferrell,et al.  Ultrasensitivity part II: multisite phosphorylation, stoichiometric inhibitors, and positive feedback. , 2014, Trends in biochemical sciences.

[20]  M. Frank-Kamenetskii,et al.  Base-stacking and base-pairing contributions into thermal stability of the DNA double helix , 2006, Nucleic acids research.

[21]  M. Heidelberger,et al.  A QUANTITATIVE STUDY OF THE PRECIPITIN REACTION BETWEEN TYPE III PNEUMOCOCCUS POLYSACCHARIDE AND PURIFIED HOMOLOGOUS ANTIBODY , 1929, Journal of Experimental Medicine.

[22]  Yong You,et al.  Stability and Mismatch Discrimination of Locked Nucleic Acid–DNA Duplexes , 2011, Biochemistry.

[23]  J. Ferrelljr,et al.  Tripping the switch fantastic: how a protein kinase cascade can convert graded inputs into switch-like outputs , 1996 .