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Current Chemical Biology

Editor-in-Chief

ISSN (Print): 2212-7968
ISSN (Online): 1872-3136

Affinity Can have Many Faces: Thermodynamic and Kinetic Properties of Ras-Effector Complex Formation

Author(s): Christina Kiel and Luis Serrano

Volume 1 , Issue 2 , 2007

Page: [215 - 225] Pages: 11

DOI: 10.2174/2212796810701020215

Price: $65

Abstract

Ras proteins belong to the superfamily of small GTP-binding proteins which have the ability to recognize and bind to several sets of effector proteins, thereby communicating signals into different pathways. Although the Ras proteins have almost identical amino acid residues in the effector binding region, and the Ras binding domains have a similar ubiquitin-like topology, the affinity constants span three orders of magnitude. Moreover, large differences in the individual enthalpic and entropic contributions are observed. Another important feature of Ras-effector interactions is the charge complementarity found between the proteins in the complex. As a result, the association rate constant is very high and contributes significantly to the affinity of the complex. Differences in binding affinities are mainly due to changes in the association rate constants with the dissociation rate constants being at a similar range. Here, we discuss the importance of understanding protein complex formation in signal transduction pathways on a molecular level, both, thermodynamically and kinetically. Although the focus is mainly on Ras-effector interactions, comparisons of different binding modes, thermodynamics and electrostatics of various effectors in complex with members of the Rho, Rab, Arf, and Ran families will also be considered. This information could be important to understand the specificity in different pathways and for a rational design of compounds which block specific pathways.

Keywords: Small GTPases, Ras proteins, protein interactions, isothermal titration calorimetry, association rate constants, electrostatic steering


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