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Assembly reflects evolution of protein complexes

Abstract

A homomer is formed by self-interacting copies of a protein unit. This is functionally important1,2, as in allostery3,4,5, and structurally crucial because mis-assembly of homomers is implicated in disease6,7. Homomers are widespread, with 50–70% of proteins with a known quaternary state assembling into such structures8,9. Despite their prevalence, their role in the evolution of cellular machinery10,11 and the potential for their use in the design of new molecular machines12,13, little is known about the mechanisms that drive formation of homomers at the level of evolution and assembly in the cell9,14. Here we present an analysis of over 5,000 unique atomic structures and show that the quaternary structure of homomers is conserved in over 70% of protein pairs sharing as little as 30% sequence identity. Where quaternary structure is not conserved among the members of a protein family, a detailed investigation revealed well-defined evolutionary pathways by which proteins transit between different quaternary structure types. Furthermore, we show by perturbing subunit interfaces within complexes and by mass spectrometry analysis15, that the (dis)assembly pathway mimics the evolutionary pathway. These data represent a molecular analogy to Haeckel’s evolutionary paradigm of embryonic development, where an intermediate in the assembly of a complex represents a form that appeared in its own evolutionary history. Our model of self-assembly allows reliable prediction of evolution and assembly of a complex solely from its crystal structure.

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Figure 1: Abundance and properties of cyclic and dihedral symmetries.
Figure 2: Routes for homomer evolution.
Figure 3: Prediction of evolutionary routes and link with (dis)assembly in solution.
Figure 4: (Dis)assembly pathways in 16 complexes.

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Acknowledgements

We thank the collaborators listed in Supplementary Table 2 for supplying the different complexes and acknowledge H. Hernandez, J. Freeke and L. Lane for assistance with mass spectrometry. We also thank C. Chothia, J. Clark and M. Babu for discussions. This work was supported by the Medical Research Council, the EMBO Young Investigators Programme, the Royal Society and the Waters Kundert Trust.

Author Contributions E.D.L., E.B.E., C.V.R. and S.A.T. designed the experiments and wrote the manuscript; E.D.L. and E.B.E. performed the bioinformatics and mass spectrometry experiments, respectively.

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Correspondence to Emmanuel D. Levy or Carol V. Robinson or Sarah A. Teichmann.

Supplementary information

Supplementary Information

The file contains Supplementary Discussions 1-2; Supplementary Figures 1-4 and Supplementary Tables 1-3. This file contains discussions on the hierarchy in interface size, and on membrane proteins; figures on conservation of QS and transitions between them, on our model of QS evolution, and on the MS protocol used for disassembly. Tables list complexes used for the evolutionary and MS analyses, and those from the literature. (PDF 818 kb)

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Levy, E., Erba, E., Robinson, C. et al. Assembly reflects evolution of protein complexes. Nature 453, 1262–1265 (2008). https://doi.org/10.1038/nature06942

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