Protein Evolution

Proteins are the most complex chemicals synthesized in nature and must fold into complicated three-dimensional structures to become active. This poses a particular challenge in explaining their evolution from non-living matter. So far, efforts to understand protein evolution have focussed on domains, independently folding units from which modern proteins are formed. Domains however are themselves too complex to have evolved de novo in an abiotic environment. We think that domains arose from the fusion of shorter, non-folding peptides, which evolved as cofactors supporting a primitive, RNA-based life form (the 'RNA world') [1]. Computationally, we are trying to reconstruct this ancient peptide set by comparative studies of modern proteins, in the same way in which ancient vocabularies were reconstructed from the comparative study of modern languages. Experimentally, we are exploring how the association of short, non-folding peptide chains may have yielded folded proteins. In particular, we are interested in the role of repetition, a process which is known to have been essential for the emergence of complexity in other biological systems. To this end, we have chosen several structurally repetitive model proteins (Fig. 1), which we are studying by means of protein biochemistry and NMR. We are also interested in several less obviously repetitive domains, particularly in double-psi b-barrels [2] and histidine kinases [3]. For double-psi barrels, we have developed a detailed evolutionary model, which suggests that they were the ancestors of aspartic proteases (Fig. 2).

Fig. 1. Proteins from pieces. Panel A shows two building block types, the αα-hairpin and the ββ-hairpin, and panel B protein domains formed by their repetition.

A. Basic Units	B. Protein Domains
αα-Hairpin	Coiled Coil	TPR repeats
ββ-Hairpin	β-Propeller	Porin

[1] Söding J, Lupas AN. (2003). More than the sum of their parts: On the evolution of proteins from peptides. Bioessays 25:837-846.

[2] Coles M, Diercks T, Liermann J, Groger A, Rockel B, Baumeister W, Koretke KK, Lupas A, Peters J, Kessler H. (1999). The solution structure of VAT-N reveals a 'missing link' in the evolution of complex enzymes from a simple babb element. Curr Biol. 9:1158-1168.

[3] Koretke KK, Volker C, Bower MJ, Lupas AN. (2003). Molecular evolution of histidine kinases. In “Histidine Kinases” (M. Inouye and R. Dutta, eds.), Academic Press.