Correlated mutations contain information about protein-protein interaction 1 1Edited by A. R. Fersht

Abstract

Many proteins have evolved to form speci®c molecular complexes and the speci®city of this interaction is essential for their function. The network of the necessary inter-residue contacts must consequently constrain the protein sequences to some extent. In other words, the sequence of an interacting protein must re¯ect the consequence of this process of adaptation. It is reasonable to assume that the sequence changes accumulated during the evolution of one of the interacting proteins must be compensated by changes in the other.Here we apply a method for detecting correlated changes in multiple sequence alignments to a set of interacting protein domains and show that positions where changes occur in a correlated fashion in the two interacting molecules tend to be close to the protein± protein interfaces. This leads to the possibility of developing a method for predicting contacting pairs of residues from the sequence alone. Such a method would not need the knowledge of the structure of the interacting proteins, and hence would be both radically different and more widely applicable than traditional docking methods.We indeed demonstrate here that the information about correlated sequence changes is suf®cient to single out the right inter-domain docking solution amongst many wrong alternatives of two-domain proteins. The same approach is also used here in one case (haemoglobin) where we attempt to predict the interface of two different proteins rather than two protein domains. Finally, we report here a prediction about the inter-domain contact regions of the heat-shock protein Hsc70 based only on sequence information. # 1997 Academic Press Limited

Coevolving protein residues: maximum likelihood identification and relationship to structure 1 1Edited by G. Von Heijne

“…In addition to their general interest for understanding the processes of protein evolution and generating hypotheses of structural interactions between residues, these observations might prove useful in both secondary and tertiary structure prediction. For example, Pazos et al (1997) have had some success predicting domain and dimer contacts using a simple methodology with low power for detecting coevolution (Pollock & Taylor, 1997), and thus the promise of enhanced signal detection of this kind is very encouraging. Including phylogenetic tree information appropriately has been helpful in other multiple sequence analysis/protein structure contexts (Goldman et al, 1996), and this approach appears to be bene®cial here, too.…”

“…There has been a great deal of recent research on methods for detecting correlated changes in protein sequence evolution (Altschuh et al 1987;Taylor & Hatrick, 1994;Gobel et al 1994;Neher, 1994;Shindyalov et al, 1994;Pollock & Taylor, 1997;Pazos et al, 1997;Chelvanayagam et al, 1997). It is expected that the residues at some sites will strongly affect the evolution of certain other sites which are close in the three-dimensional structure of the protein.…”

“…Studies attempting to identify correlated changes have, however, met with only limited success in identifying pairs of sites which are adjacent in the three-dimensional structure (although potentially better results are obtained when applied to docking; Pazos et al, 1997). There are a number of complications which could account for this failure, including the possibilities that: (1) distant sites may be as important as adjacent sites in the compensatory process; (2) the number of sites involved in compensation is so large that the pairwise correlation signal is too small to be detected; (3) the coevolutionary relationships between sites change too quickly with evolutionary time; or (4) the methods used are insuf®cient for separating correlation in the evolutionary process (coevolution) from background noise (false correlation due to random events).…”

Coevolution of gene expression among interacting proteins

“…[1][2][3][4][5][6][7][8]. The identification of coevolving pairs of genes is interesting and important for several reasons.…”

Gene phylogenies and protein–protein interactions: possible artifacts resulting from shared protein interaction partners

“…Similar approaches have been attempted on protein structures [20], albeit with less general applicability due to correlation chaining effects [10,6]. Analogously, correlated mutations in different proteins contain information about protein-protein interaction [16,15]. Correlated rates of evolution can therefore be employed to discover protein-protein interactions [21].…”