The polytopic helical membrane proteome is dominated by proteins containing seven transmembrane helices (7TMHs). They cannot be grouped under a monolithic fold or superfold. However, a parallel structural analysis of folds around that magic number of seven in distinct protein superfamilies (SWEET, PnuC, TRIC, FocA, Aquaporin, GPCRs) reveals a common homology, not in their structural fold, but in their systematic pseudo-symmetric construction during their evolution. Our analysis leads to guiding principles of intragenic duplication and pseudo-symmetric assembly of ancestral transmembrane helical protodomains, consisting of 3 (or 4) helices. A parallel deconstruction and reconstruction of these domains provides a structural and mechanistic framework for their evolutionary paths. It highlights the conformational plasticity inherent to fold formation itself, the role of structural as well as functional constraints in shaping that fold, and the usefulness of protodomains as a tool to probe convergent vs divergent evolution. In the case of FocA vs. Aquaporin, this protodomain analysis sheds new light on their potential divergent evolution at the protodomain level followed by duplication and parallel evolution of the two folds. GPCR domains, whose function does not seem to require symmetry, nevertheless exhibit structural pseudo-symmetry. Their construction follows the same protodomain assembly as any other pseudo-symmetric protein suggesting their potential evolutionary origins. Interestingly, all the 6/7/8TMH pseudo-symmetric folds in this study also assemble as oligomeric forms in the membrane, emphasizing the role of symmetry in evolution, revealing self-assembly and co-evolution not only at the protodomain level but also at the domain level.

多面螺旋膜蛋白质组主要由含有七个跨膜螺旋 (7TMHs) 的蛋白质组成。它们不能在整体折叠或超级折叠下分组。然而，对不同蛋白质超家族（SWEET、PnuC、TRIC、FocA、Aquaporin、GPCRs）中神奇数字 7 周围折叠的平行结构分析揭示了一个共同的同源性，不是在它们的结构折叠中，而是在它们系统的伪对称结构中在他们的进化过程中。我们的分析得出了祖先跨膜螺旋原域的基因内重复和伪对称组装的指导原则，由 3（或 4）个螺旋组成。这些领域的并行解构和重建为其进化路径提供了结构和机械框架。它强调了折叠形成本身固有的构象可塑性，结构和功能约束在形成折叠中的作用，以及原域作为探测收敛与发散进化的工具的有用性。在 FocA 与 Aquaporin 的情况下，这种原域分析揭示了它们在原域水平上的潜在发散进化，然后是两个折叠的重复和平行进化。GPCR 域的功能似乎不需要对称性，但仍表现出结构假对称性。它们的构建遵循与任何其他伪对称蛋白质相同的原始域组装，表明它们的潜在进化起源。有趣的是，本研究中的所有 6/7/8TMH 假对称折叠也在膜中组装为寡聚形式，