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Evolutionary relationship of two ancient protein superfolds


Proteins are the molecular machines of the cell that fold into specific three-dimensional structures to fulfill their functions. To improve our understanding of how the structure and function of proteins arises, it is crucial to understand how evolution has generated the structural diversity we observe today. Classically, proteins that adopt different folds are considered to be nonhomologous. However, using state-of-the-art tools for homology detection, we found evidence of homology between proteins of two ancient and highly populated protein folds, the (βα)8-barrel and the flavodoxin-like fold. We detected a family of sequences that show intermediate features between both folds and determined what is to our knowledge the first representative crystal structure of one of its members, giving new insights into the evolutionary link of two of the earliest folds. Our findings contribute to an emergent vision where protein superfolds share common ancestry and encourage further approaches to complete the mapping of structure space onto sequence space.

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Figure 1: The sequence spaces populated by the (βα)8-barrel and the flavodoxin-like fold interface considerably.
Figure 2: Clustering reveals a family of intermediate sequences that are equally related to the (βα)8-barrel and the flavodoxin-like fold.
Figure 3: The X-ray crystal structure of N-TM0182 reveals a swapped dimer.
Figure 4: A structure-based sequence alignment reveals a fragment of highest similarity.
Figure 5: The conserved (αβ)2 fragment of N-TM0182 can be superimposed multiple times on the (βα)8-barrel fold with similar scores.

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We thank S. Toledo-Patiño, V. Alva and J. Söding for discussions. We are grateful to the crystallography community at the Max Planck Institute for their support. This work was supported by Deutsche Forschungsgemeinschaft grant HO 4022/1-2.

Author information




J.A.F.-R. and B.H. designed the research; J.A.F.-R. performed the experiments; J.A.F.-R., S.S. and B.H. analyzed the data; and J.A.F.-R. and B.H. wrote the manuscript.

Corresponding author

Correspondence to Birte Höcker.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Figures 1–7 and Supplementary Tables 1 and 2. (PDF 13146 kb)

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Farías-Rico, J., Schmidt, S. & Höcker, B. Evolutionary relationship of two ancient protein superfolds. Nat Chem Biol 10, 710–715 (2014).

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