Burstein and Colleagues Advance Understanding of Complex Molecular Process

Ezra Burstein, M.D., Ph.D., a Professor and Chief of Digestive and Liver Diseases, and colleagues recently published the results of an investigation into the molecular organization of essential regulators of endosomal recycling, a process required for normal functioning of all cells. The study, which appears in the December issue of Nature Structure and Molecular Biology, builds on nearly two decades of work in the Burstein Lab, starting with the discovery of a family of proteins known as COMMD.

We asked Dr. Burstein to summarize the research and its significance.

In this study, we report the molecular organization of critical regulators of endosomal recycling, a process required for normal function of all cells. The plasma membrane of the cell is an essential barrier between the environment and the inside machinery of the cell. It is not only a membrane, but it includes a number of essential proteins including receptors, transporters, channels, and myriad other factors, which represent nearly 11% of all proteins in human cells. Normal cell function requires a constant flux of membranes from the cell surface to intracellular vesicles known as endosomes. Plasma membrane proteins are included in these membranes. From endosomes, these proteins are sent back to the plasma membrane for recycling or routed to lysosomes for degradation. Given the indispensable functions of many plasma membrane proteins, the process of endosomal recycling is essential to cellular homeostasis. The paper describes the molecular organization of the Retriever complex, an essential regular of endosomal recycling, as well as its closely associated partner, the COMMD/CCDC22/CCDC93 or CCC complex. With 16 distinct protein subunits, this structure is complex and deciphering its organization allows us for the first time to begin to understand how this system works at the molecular level. 

Many aspects of normal health are dependent on normal function of the Retriever and CCC complex. For example, inherited mutations damaging components of this system lead to elevated cholesterol, alterations in copper handling in the body, and altered intrauterine development resulting in a congenital condition known as Ritscher-Schinzel syndrome. As part of the studies published, the group also reported for the first time that some cancer types frequently harbor mutations that inactivate the Retriever complex, resulting in significant changes in plasma membrane proteins. The study is the result of a close partnership with Dr. Stone Chen, Associate Professor at Iowa State University, as well as Dr. James Chen, Professor in the Department of Biophysics at UT Southwestern, co-corresponding authors on the paper. This work builds on nearly two decades of work in the Burstein lab, starting with the discovery of the family of proteins known as COMMD proteins nearly 20 years. AlphaFold, a computational method based on artificial intelligence that can predict protein folding based on amino acid sequences, as well as the advent of cryogenic electron microscopy, made these studies possible.