Research on Membrane Proteins Leads to a New Way to Study Protein Interactions

In a new Journal of Biological Chemistry paper, Kalina Hristova‘s research group presents a new methodology for the study of membrane protein interactions, alongside experimental data about the membrane proteins that regulate skeletal development. This new methodology represents an advance for membrane protein research, which has been limited by the capabilities of currently available experimental techniques. The researchers’ experimental results uncover previously unknown physical properties of membrane protein interactions, which may guide the development of more effective therapeutics for developmental disorders and cancers.

In the paper, Del Piccolo et al. focus on Receptor Tyrosine Kinases (RTKs), the second largest class of membrane proteins and a common drug target. Activation of RTKs involves binding of an external stimuli to the receptor, lateral association of two receptors, and intracellular biological activity. Kalina Hristova’s research group is known for developing and implementing novel quantitative fluorescence microscopy techniques to measure the thermodynamics of lateral association of receptors, a process that is one predictor of RTK activation. Lateral association takes place between either two identical receptors (aka homodimerization), which has been well-studied, or two non-identical receptors (aka heterodimerization), which remains largely uncharacterized due to experimental limitations.

The new paper leverages the Hristova research group’s microscopy techniques to examine the uncharacterized RTK heterodimer. First, the researchers develop a theoretical model to describe the thermodynamics of RTK heterodimerization. Then, they apply this model to experimental data on the interactions of Fibroblast Growth Factor Receptors (FGFRs), the family of RTKs responsible for skeletal development. They show that the propensity for FGFR heterodimerization is similar to the propensity for FGFR homodimerization, and that two separate pathogenic point mutations can stabilize FGFR heterodimers. This indicates that all possible receptor interactions must be considered in analyses of FGFR function and the development of therapeutics. Thus, the researchers demonstrate that the methodology they present can yield new knowledge about RTK interactions and can further our understanding of the RTK activation process.

 

The paper is a large portion of first author Nuala Del Piccolo’s PhD dissertation, which she successfully defended on December 1. Del Piccolo’s contributions included developing the theoretical model, performing microscopy experiments, writing software to fit the model to the data, and writing the paper.