Print Page  

Protein evolution

Andrei Lupas

Andrei Lupas

  • PhD in Molecular Biology at Princeton University, 1985-91
  • Postdoctoral training at the Gene Center of the University of Munich and at the MPI for Biochemistry, Martinsried, 1993-97
  • Senior Computational Biologist and Assistant Director of Bioinformatics at SmithKline Beecham Pharmaceuticals, 1997-2001
  • Director at the MPI since 2001

Research Interest

Since proteins are essential components of living cells, it is hardly surprising that precursors of most proteins observed today existed at the time of the last common ancestor of all life. But how did proteins evolve? Randomly synthesized polypeptide chains form folded structures in less than one in a billion cases, so it seems impossible that proteins evolved by chance. Our hypothesis is that folded proteins evolved by fusion and recombination of an ancestral set of peptides which emerged as cofactors in the primordial “RNA world”. Using cutting-edge bioinformatic tools, as well as experimental approaches including protein biochemistry, spectroscopy and structural biology (crystallography and NMR), our aim is to describe this peptide set just as ancient vocabularies have been reconstructed from comparative analysis of modern languages.

We are also studying how changes in protein structure create new functionality, focusing on how type I receptors transduce signals across membranes and AAA ATPases disassemble, unfold and translocate proteins. We are using model organisms to study the genetic processes leading to changes in protein fold topology or the evolution of entirely new folded proteins. Finally, we are working towards a system of protein classification by natural descent, eliminating the analogous criteria used in current classification systems.

Selected Reading

1) Söding J, Lupas AN. (2003) More than the sum of their parts: on the evolution of proteins from peptides. Bioessays 25, 837-46.

2) Alva V, Koretke KK, Coles M, Lupas AN. (2008) Cradle-loop barrels and the concept of metafolds in protein classification by natural descent. Curr Opin Struct Biol 18, 358-65.

3) Dunin-Horkawicz S, Lupas AN. (2010) Comprehensive Analysis of HAMP Domains: Implications for Transmembrane Signal Transduction. J Mol Biol 397, 1156-74.
(click to enlarge)
A galaxy of folds. Proteins of known structure were clustered by their sequence similarity and colored by their structural class: all-α (blue), all-β (cyan), α/β (red), α+β (yellow), small proteins (green), multi-domain proteins (orange), and membrane proteins (magenta).
(click to enlarge)
The cradle-loop barrel metafold. The different folds within the metafold are connected by arrows according to their presumed descent. Red arrows connect folds whose common descent is substantiated both computationally and experimentally.