Detecting the Coevolution in and among Protein Domains

Abstract

Correlated changes of nucleic or amino acids have provided strong information about the structures and interactions of molecules. Despite the rich literature in coevolutionary sequence analysis, previous methods often have to trade off between generality, simplicity, phylogenetic information, and specific knowledge about interactions. Furthermore, despite the evidence of coevolution in selected protein families, a comprehensive screening of coevolution among all protein domains is still lacking. We propose an augmented continuous-time Markov process model for sequence coevolution. The model can handle different types of interactions, incorporate phylogenetic information and sequence substitution, has only one extra free parameter, and requires no knowledge about interaction rules. We employ this model to large-scale screenings on the entire protein domain database (Pfam). Strikingly, with 0.1 trillion tests executed, the majority of the inferred coevolving protein domains are functionally related, and the coevolving amino acid residues are spatially coupled. Moreover, many of the coevolving positions are located at functionally important sites of proteins/protein complexes, such as the subunit linkers of superoxide dismutase, the tRNA binding sites of ribosomes, the DNA binding region of RNA polymerase, and the active and ligand binding sites of various enzymes. The results suggest sequence coevolution manifests structural and functional constraints of proteins. The intricate relations between sequence coevolution and various selective constraints are worth pursuing at a deeper level.

Weak Selection and Protein Evolution

“…Several early studies identified within-protein correlations among amino acid positions but did not account for phylogenetic relationships (Korber et al 1993;Neher 1994). More recent studies have identified co-occurring substitutions within a phylogeny (Pollock 1999;Fukami-Kobayashi et al 2002;Dimmic et al 2005;Dutheil et al 2005;Yeang and Haussler 2007). Such patterns support within-protein epistatic interactions but do not distinguish among CN, CM, and CWS scenarios.…”

Coordinated Rates of Evolution between Interacting Plastid and Nuclear Genes in Geraniaceae

“…Structurally mediated coevolution of any amino acid site is then evaluated using the substitution vector and a cluster-based approach (Dutheil and Galtier, 2007). Another approach studies the coevolved amino acids by incorporating a continuous-time Markov process model (Yeang and Haussler, 2007). Both of these approaches agree well with experimental results; however, the latter approach is computationally demanding and therefore more feasible for studies of small protein domains.…”

A Survey on Evolutionary Analysis in PPI Networks

“…Nevertheless, other studies have been able to predict interacting domains from co-evolving residues between domains or proteins (see e.g. Jothi et al, 2006;Yeang & Haussler, 2007) indicating that different organisms use the same 'building blocks' for PPIs and that the functionality of many domain pairs in mediating protein interactions is maintained in evolution (Itzhaki et al, 2006). Another perspective on co-evolution of interacting partners was given by Mintseris & Weng (2005), who distinguished between transient and obligate interactions.…”