Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Chemistry and Biochemistry, California State University, Northridge, CA, USA.
J Mol Evol. 2020 May;88(4):319-344. doi: 10.1007/s00239-020-09934-4. Epub 2020 Mar 18.
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.
多拓扑螺旋膜蛋白组主要由含有七个跨膜螺旋 (7TMHs) 的蛋白质组成。它们不能被归为一个整体折叠或超折叠。然而，对不同蛋白质超家族（SWEET、PnuC、TRIC、FocA、Aquaporin、GPCRs）中围绕这个神奇的七字数字的折叠进行平行结构分析，揭示了一种共同的同源性，不是在它们的结构折叠中，而是在它们进化过程中的系统拟对称结构中。我们的分析导致了指导原则的产生，即在基因内重复和拟对称组装祖先跨膜螺旋原结构域，由 3（或 4）个螺旋组成。对这些结构域的平行解构和重建提供了一个结构和机制框架，用于它们的进化路径。它突出了折叠形成本身所固有的构象灵活性，结构和功能约束在塑造该折叠中的作用，以及原结构域作为探测趋同进化与分歧进化的工具的有用性。在 FocA 与 Aquaporin 的情况下，这种原结构域分析揭示了它们在原结构域水平上潜在的分歧进化，然后是两个折叠的复制和并行进化。GPCR 结构域的功能似乎不需要对称，但表现出结构拟对称。它们的结构遵循与任何其他拟对称蛋白质相同的原结构域组装，这表明了它们的潜在进化起源。有趣的是，本研究中的所有 6/7/8TMH 拟对称折叠在膜中也以寡聚形式组装，强调了对称在进化中的作用，揭示了自组装和共同进化不仅在原结构域水平，而且在结构域水平上的作用。
