Residues crucial for maintaining short paths in network communication mediate signaling in proteins

Abstract

Here, we represent protein structures as residue interacting networks, which are assumed to involve a permanent flow of information between amino acids. By removal of nodes from the protein network, we identify fold centrally conserved residues, which are crucial for sustaining the shortest pathways and thus play key roles in long-range interactions. Analysis of seven protein families (myoglobins, G-protein-coupled receptors, the trypsin class of serine proteases, hemoglobins, oligosaccharide phosphorylases, nuclear receptor ligand-binding domains and retroviral proteases) confirms that experimentally many of these residues are important for allosteric communication.The agreement between the centrally conserved residues, which are key in preserving short path lengths, and residues experimentally suggested to mediate signaling further illustrates that topology plays an important role in network communication. Protein folds have evolved under constraints imposed by function. To maintain function, protein structures need to be robust to mutational events. On the other hand, robustness is accompanied by an extreme sensitivity at some crucial sites. Thus, here we propose that centrally conserved residues, whose removal increases the characteristic path length in protein networks, may relate to the system fragility.

Coarse-grained modeling of allosteric regulation in protein receptors

“…The more rigid protein core residues are not identified in the allosteric maps at this level of coarse-graining, indicating that multiscale modeling may be needed to identify those residues. The theoretically identified allosteric sites are also consistent with the sequence-based analysis of Ranganathan et al (36) [residues 113, 293-295, 299, and 302 (301 in our analysis)] and with the topology-based analysis of Nussinov et al (38) (residues 67, 301, and 312). Although the predictions of the different models are not identical, they are consistent and successful in capturing the key allosteric sites, including the ligand environment and the G-protein binding site.…”

“…Allosteric Sites. The allosteric sites predicted from our model, from bioinformatics analysis of conserved residues (36,38), and obtained in experiments (21) are shown in Fig. 2 E and F. In rhodopsin (Fig.…”

“…Normal mode analysis (NMA) based on coarse-grained (CG) protein models successfully described allostery in a variety of molecular machines that exhibit large-scale conformational transitions (28)(29)(30)(31)(32)(33)(34)(35), but these methods are less suited for studying subtle structural changes that mediate signaling (13)(14)(15). Although bioinformatics methods based on the analysis of conserved amino acids in the receptor sequence (36)(37)(38) identify some allosteric sites, these methods do not provide a direct mechanistic link between structure and allostery. Therefore, developing a theoretical description of allosteric regulation in signaling ultimately requires new strategies.…”

Dynamical networks in tRNA:protein complexes

“…The contribution of each residue or node to the characteristic path length (CPL), defined as an average of the shortest path length between all pairs of nodes in the network, provides an estimate of the effect of node connectivity on communication pathways in a protein. Conserved residues that greatly affect the CPL upon removal have been hypothesized to be important for allosteric signal transmission (10). Snapshots from a short simulation of a modeled MetRS:tRNA complex indicated that the shortest path between protein residues interacting with the anticodon and the adenylate binding site was sensitive to conformational changes in the protein (11), but the tRNA and contacts with other identity elements on the tRNA were neglected in their study of the signal transmission.…”

Understanding large multiprotein complexes: applying a multiple allosteric networks model to explain the function of the Mediator transcription complex

“…In fact, there have been several statistical modelings of individual proteins as networks (Amitai et al, 2004;del Sol et al, 2006;del Sol and O'Meara, 2005;Greene and Higman, 2003). Also, for allosteric changes in a protein to occur, residues involved in the allosteric pathway within each protein subunit are predicted to be energetically coupled and evolutionarily co-evolving (Lockless and Ranganathan, 1999).…”