Understanding the structural basis of transmembrane association with a multidisciplinary strategy

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

This award from the Chemistry of Life Processes Program in the Chemistry Division funds Professors Alessandro Senes and Aaron Hoskins. The project investigates the factors that stabilize proteins located in the membrane of a cell. Some of these proteins are called transmembrane proteins since they cross the entire cell membrane. Membrane proteins represent 20-40% of all proteins. They are responsible for a variety of vital cellular functions, such as: transport, signaling, adhesion, development, and many regulatory processes. This research project examines the factors that lead to transmembrane stability and the function of specific membrane proteins. Professors Senes and Hoskins design courses that offer an introduction to bioinformatics, including a variety of topics in biochemistry (genomics, proteomics, systems biology, structure/prediction) and computational methods (and hand-on experience). The objective of this course is to create awareness and interest in computational biology. The team also develops an interactive computational biology module for high-school students focused on the quantitative aspects of biology and the importance of integrating computation with experiments. This project involves computational structure prediction, and high-throughput interaction studies, as well as single-molecule biophysics. The structural centerpiece is a computational method that can predict the structure of GASright dimers with good confidence and precision. GASright is best known as the fold of the glycophorin A dimer (GpA), the major model system for TM helix association. The name GASright originates from the right-handed crossing angle between the helices (near -40°), and from the characteristic small amino acids (Gly, Ala, Ser: GAS) at its interface, which are arranged to form GxxxG and GxxxG-like patterns (GxxxA, AxxxG, etc.). The computational method is used to identify GASright candidates among thousands of protein sequences of transmembrane helices for high-throughput experimental analysis. The resulting data produces a quantitative model of GASright association energetics, which is then tested in vitro on a small set of selected proteins. Overall, the research represents a large-scale structure-based analysis of transmembrane helix association that may produce a quantitative model of stability and specificity for GASright.