Systematic Analysis of Symmetry in Membrane Proteins

Abstract

Membrane proteins are encoded by around one third of a given genome, and play key roles in transmission of information and chemicals such as neurotransmitters into the cell. Available membrane protein structures have revealed an abundance of symmetry and pseudo-symmetry, which are observed not only in the formation of multi-subunit assemblies, but also in the repetition of internal structural elements. Secondary active transporters provide striking examples of the functional significance of symmetry. For instance, the structures of many transporters consist of two pseudo-symmetric repeats with opposite transmembrane orientations. These repeats can form asymmetric conformations to create a pathway to one side of the membrane, consistent with the so-called alternating access hypothesis. By having one repeat adopt the conformation of the second repeat and vice-versa, the protein can create a new asymmetric structure that is open to the opposite side of the membrane. This “asymmetry exchange” underlies rocking-bundle or elevator-like movements that result in the transport of a substrate. In this context, a systematic study of symmetry should provide a framework for a broader understanding of the mechanistic principles and evolutionary development of membrane proteins. However, existing analyses lack the detail and breadth required for such a systematic study. Therefore, in this project we aim to quantify both the extent and diversity of symmetry relationships in known structures of membrane proteins. To achieve this task, we combine the output of two programs for symmetry detection, namely SymD and CE-Symm, each of which has certain limitations. Our approach also allows us to explore the characteristics that discriminate symmetric from pseudo-symmetric or asymmetric structures. We anticipate that this analysis will provide a valuable foundation for addressing a wide range of questions relating to the function and evolution of these important proteins.