Our research focuses on understanding oligomeric complexes of single-pass membrane proteins. The single-pass proteins are the largest class, comprising over 20% of all membrane proteins. They are of extreme biological importance: the human proteome alone contains over 2,000 single-pass membrane proteins which are central to a myriad of physiological functions. The transmembrane helices of these single-pass membrane proteins often play a critical role through oligomerization and conformational change. Understanding the structural and biophysical basis these phenomena is critical to understanding function in biological processes, and the mechanisms of many diseases. My laboratory studies oligomerization of single-pass membrane proteins with two complementary projects ? one related to elucidating structure-function relationship in an important biological system, the second aiming to understand the general principles of transmembrane helix association. Because these membrane protein systems are difficult to study with the traditional structural methods, we apply a methodology that integrates experimental methods with advanced computational modeling. The computational modeling mitigates the lack of experimental structure, providing structural interpretation of the available experimental data and guidance for experimental designs. The goal of our first project is to investigate the structural organization of membrane proteins of the divisome, the large multi-protein that governs cell division in bacteria. Although progress has been achieved in understanding its components and their roles, the structural architecture of the divisome and its precise mechanisms are still poorly understood. Unraveling this organization is crucial for understanding the mechanisms that govern bacterial division. This knowledge could also support the development of new strategies for controlling bacterial growth. Our second project seeks to understand transmembrane helix oligomerization using protein design. The subject is one of the most common transmembrane dimerization motifs, the GASright motif. GASright ? which is best known as the fold of the glycophorin A dimer ? is characterized by the presence of small amino at its interface, arranged to form GxxxG and similar patterns. The helices are in close contact, promoting the formation of networks of weak C??H???O=C hydrogen bonds. We are able to predict computationally the structure of GASright dimers and their relative stability. Our next goal is to test our theories by modulating dimerization and conformational switching in these dimers through the design of ligand binding sites. This is an almost unexplored area of membrane protein engineering that is extremely relevant for natural systems and could potentially have applications in synthetic biology.
This project seeks to understand the physical factors that govern the association of transmembrane helices and the function of biological membrane protein complexes, using a combination of advanced experimental and computational methods. Membrane proteins represent approximately 20-40% of all proteins and are responsible for myriad essential cellular functions. Understanding the principles that govern the assembly of membrane protein association is not only paramount for investigating their function, but also to reveal how assembly defects may result in human disease.
