Pseudo-Symmetric Assembly of Protodomains as a Common Denominator in the Evolution of Polytopic Helical Membrane Proteins

Abstract

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 pseudosymmetry. 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.

Using iCn3D and the World Wide Web for structure-based collaborative research: Analyzing molecular interactions at the root of COVID-19

“…These URLs are "lifelong" and can be accessed from a preprint or a publication. We started to publish 3D analyses as links 1,6 . This paper further demonstrates its use with links that annotate structures and molecular interactions between SARS-COV-2 and the human ACE2 receptor, or with antibodies.…”

“…This is the 3rd function of iCn3D: providing a capability to share structural analysis and annotations with collaborators and peers and use them in publications. These links are in fact already used today by a number of professors in teaching about protein structure and molecular interactions, and we envision them as being used for peer review and publication, as we have started to do ourselves in our latest preprints and papers 1,6 .…”

Topological and Structural Plasticity of the single Ig fold and the double Ig fold present in CD19

“…The copyright holder for this preprint (which this version posted June 5, 2021. ; https://doi.org/10.1101/2021.06.04.447059 doi: bioRxiv preprint have described previously in pseudo symmetric polytopic membrane protein formation (Youkharibache, Tran, and Abrol 2020).…”

“…20% of known protein folds/domains are pseudo-symmetric (Myers-Turnbull et al 2014) and that in each structural class (Lo Conte et al 2000) the most diversified fold exhibits pseudo symmetry, suggesting a link between symmetry and evolution. In particular, two classes of folds show a higher proportion of pseudo-symmetric domains: membrane proteins, with for example GPCRs (Youkharibache, Tran, and Abrol 2020), and beta folds, with chief among them the Ig-fold (Youkharibache 2019). The Ig-fold is present in over 2% of human genes in the human genome (Lander et al 2001) and it is overly represented in the surfaceome/immunome (Bausch-Fluck, Milani, and Wollscheid 2019;Díaz-Ramos, Engel, and Bastos 2011).…”

Molecular basis for KDEL-mediated retrieval of escaped ER-resident proteins – SWEET talking the COPs

“…The fusion of the two THBs – creating a new seven-TM transporter – enabled the PQ-loop fold to evolve new functions, as mutations could now occur separately in the two three-TM-bundles ( Feng and Frommer, 2016 ). Indeed, in recent years, the fusion of simple three-TM, four-TM or five-TM bundles has emerged as a hallmark of SLC and receptor evolution ( Forrest, 2015 ; Youkharibache et al, 2020 ). As is the case in the seven-TM PQ-loop transporter and the KDELR, the THBs are inverted 180° relative to one another within the membrane ( Fig.…”