The origin, evolution and structure of the protein world

Gustavo Caetano-Anollés, Minglei Wang, Derek Caetano-Anollés, Jay E. Mittenthal

Research output: Contribution to journalReview articlepeer-review


Contemporary protein architectures can be regarded as molecular fossils, historical imprints that mark important milestones in the history of life. Whereas sequences change at a considerable pace, higher-order structures are constrained by the energetic landscape of protein folding, the exploration of sequence and structure space, and complex interactions mediated by the proteostasis and proteolytic machineries of the cell. The survey of architectures in the living world that was fuelled by recent structural genomic initiatives has been summarized in protein classification schemes, and the overall structure of fold space explored with novel bioinformatic approaches. However, metrics of general structural comparison have not yet unified architectural complexity using the 'shared and derived' tenet of evolutionary analysis. In contrast, a shift of focus from molecules to proteomes and a census of protein structure in fully sequenced genomes were able to uncover global evolutionary patterns in the structure of proteins. Timelines of discovery of architectures and functions unfolded episodes of specialization, reductive evolutionary tendencies of architectural repertoires in proteomes and the rise of modularity in the protein world. They revealed a biologically complex ancestral proteome and the early origin of the archaeal lineage. Studies also identified an origin of the protein world in enzymes of nucleotide metabolism harbouring the P-loop-containing triphosphate hydrolase fold and the explosive discovery of metabolic functions that recapitulated well-defined prebiotic shells and involved the recruitment of structures and functions. These observations have important implications for origins of modern biochemistry and diversification of life.

Original languageEnglish (US)
Pages (from-to)621-637
Number of pages17
JournalBiochemical Journal
Issue number3
StatePublished - Feb 1 2009


  • Evolution
  • Fold superfamily
  • Organismal diversification
  • Protein domain
  • Proteome
  • Tripartite world

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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