Pseudo-Symmetry and Conformational Plasticity in 7 Transmembrane Helix (7TMH) Proteins: Intragenic Duplication and Assembly of 3TMH or 4TMH Protodomains with Evolutionary Balance of Structural Constraints and Functional Divergence
Membrane proteins sharing 7 transmembrane helices (7-TMH) dominate the polytopic TMH proteome. They cannot be grouped under a monolithic fold or superfold, however, a parallel structural analysis of folds around that magic number of 7-TMH in distinct 6/7/8-TMH protein superfamilies (SWEET, PnuC, TRIC, FocA, Aquaporin, GPCRs, AND MFS), reveals a common homology, not in their structural fold, but in their systematic pseudo-symmetric construction. Our analysis leads to guiding principles of intragenic duplication and pseudo-symmetric assembly of ancestral 3 or 4 Transmembrane Helix (3/4-TMH) protodomains/protofolds. A parallel deconstruction and reconstruction of these domains provides a structural and mechanistic framework for the evolution path of current pseudo-symmetrical transmembrane helical (TMH) proteins. It highlights the conformational plasticity inherent to fold formation itself. The sequence/structure analysis of different 6/7/8-TMH superfamilies provides a unifying theme of their evolutionary process involving the intragenic duplication of protodomains with varying degrees of sequence and fold divergence under conformational and functional constraints.