Computational studies of membrane transport proteins

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

Secondary active transporters are a class of proteins found in cell membranes. They use existing differences in the concentration of molecules as a source of energy to move other substances, like nutrients or neurotransmitters, against their natural flow. This process requires the protein to change shape and expose a pathway that allows access by the substance from one or other side of the membrane, in a cycle called alternating access. Every organism contains dozens of different types of these transporter proteins. They have various designs, but they all have an internal pattern of symmetry. Recent discoveries have emerged from looking at their 3D shapes, which can be determined using modern electron microscopes. Nevertheless, to truly understand how each transporter works and how it is affected by its surroundings, we need to know more about the different shapes it can morph into and where it binds the substances that it moves. In addition, regions at the start and end of these proteins, which play important roles in cellular control of their transport behaviors, are highly flexible which requires the development of novel approaches to describe. This year we published an important study of a membrane transport protein, in close collaboration with structural biologists and biochemists. Specifically, we focused on a protein that is key for conversion of food into cellular energy by allowing a metabolite called pyruvate to enter mitochondria. While our collaborators determined snapshots of the structure of this protein (the mitochondrial pyruvate carrier, MPC), we predicted its dynamics throughout the functional cycle using advanced machine learning techniques. We also predicted how pyruvate interacts with the protein and provided an explanation for the energetic driving force for mitochondrial entry using excess protons. Finally, the structures presented in this work illustrate interactions with therapeutic drugs that are currently of interest for treating diabetes, cancer and Parkinson's disease.