Beta-Strand Interfaces of Non-Dimeric Protein Oligomers Are Characterized by Scattered Charged Residue Patterns

Abstract

Protein oligomers are formed either permanently, transiently or even by default. The protein chains are associated through intermolecular interactions constituting the protein interface. The protein interfaces of 40 soluble protein oligomers of stœchiometries above two are investigated using a quantitative and qualitative methodology, which analyzes the x-ray structures of the protein oligomers and considers their interfaces as interaction networks. The protein oligomers of the dataset share the same geometry of interface, made by the association of two individual β-strands (β-interfaces), but are otherwise unrelated. The results show that the β-interfaces are made of two interdigitated interaction networks. One of them involves interactions between main chain atoms (backbone network) while the other involves interactions between side chain and backbone atoms or between only side chain atoms (side chain network). Each one has its own characteristics which can be associated to a distinct role. The secondary structure of the β-interfaces is implemented through the backbone networks which are enriched with the hydrophobic amino acids favored in intramolecular β-sheets (MCWIV). The intermolecular specificity is provided by the side chain networks via positioning different types of charged residues at the extremities (arginine) and in the middle (glutamic acid and histidine) of the interface. Such charge distribution helps discriminating between sequences of intermolecular β-strands, of intramolecular β-strands and of β-strands forming β-amyloid fibers. This might open new venues for drug designs and predictive tool developments. Moreover, the β-strands of the cholera toxin B subunit interface, when produced individually as synthetic peptides, are capable of inhibiting the assembly of the toxin into pentamers. Thus, their sequences contain the features necessary for a β-interface formation. Such β-strands could be considered as ‘assemblons’, independent associating units, by homology to the foldons (independent folding unit). Such property would be extremely valuable in term of assembly inhibitory drug development.

Intermolecular β-Strand Networks Avoid Hub Residues and Favor Low Interconnectedness: A Potential Protection Mechanism against Chain Dissociation upon Mutation

“…We have shown that this distinction is necessary to exhibit features of intermolecular β-strands [32]. This is certainly related to the involvement of the backbone interactions in the hydrogen bond network of the β-sheets while in α-helices such backbone interactions are involved intramolecularly and are not interfering with intermolecular interactions.…”

Geometry and Topology in Protein Interfaces -- Some Tools for Investigations

“…Statistical analyses have been performed on the case of the β interfaces, that are formed by two adjacent β strands, one from each subunit [6][7][8]. In [8] the analysis has been extended to a dataset of 755 proteins.…”

“…In other words, the backbone hydrogen bonds satisfy the mathematical property of symmetrically minimized distances and the backbone non-hydrogen atoms that engage in BB hydrogen bonds are reciprocal nearest neighbours, with the indicated accuracy. This identification has been obtained using the web server RING (see Methods) to calculate the hydrogen bonds and compare with the graphs (see also [6]). Among the 120 pairs of residues in the graphs (anti-parallel and parallel cases only), 108 are recognized by RING as hydrogen bonds and 12 are not.…”

“…The analysis will proceed with the inspection and comparison of the interaction graphs of the level 1 of the interface, with some additional information from the level 2. The focus will be on the topology, namely on the organisation of edges in the graphs, whose importance has already been shown in the previous publications [6,11]. As already stated, the amino acid resolution will be systematically adopted.…”

“…From the previous examples, there is no surprise in claiming that the geometry will provide information on the interactions at the interfaces. In our previous publications [6][7][8], careful statistical analyses have been performed and have led to formulate constraints on the amino acid sequences and atom pairs that are compatible with a given geometrical form. The long term perspective of our work is to rationalize the interface, namely to establish a clear understanding of its sequence-structure relationship, in order to develop interface prediction tools and help to advance in interface design.…”