Medical Research

Washington University in St. Louis

Weikai Li, Rui Zhang
St. Louis, MO
December 2018

Structure determines function.  A new protein structure is often the milestone that transforms our understanding of basic biological processes.  Four Nobel Prizes have been awarded to the scientists who deciphered the structures of membrane proteins, which constitute about one third of all proteins.  Membrane proteins, however, are notoriously difficult for structural studies due to their hydrophobicity and instability.  The structures of only ~2% of human membrane proteins have been solved, significantly impeding the understanding of their functions.  New out-of-the-box approaches for determining their structures would be nothing short of revolutionary for science and medicine.  Two investigators at Washington University in St. Louis propose a “termini coupling” method to stabilize membrane proteins for purification and structural determination.  Building upon their recent success applying termini coupling to X-ray crystallography, they will develop this novel concept for cryo-electron microscopy, a revolutionary structural tool that overcomes many limitations of crystallography.  The team’s proposed approach can be universally applied to solve the structures of almost any membrane protein, which will allow them and others to address fundamental questions about the multitude of processes that occur on or through cell membranes.  The structures will reveal how signals move between the external and internal environment, how nutrients and ions are sensed and transported, how enzymes catalyze reactions at the membrane interface, and how cells identify and interact with each other to execute a coordinated action.  Termini coupling will allow scientists to finally ‘see’ how human membrane proteins are built and how their functions are executed.  Termini coupling is expected to fundamentally transform the current understanding of biology.

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