Using HMM-HMM profile comparisons and structure modelling, we assessed the existence of a tandem BRCT in both Nbs1 and Xrs2 after the FHA. The structure-based conservation analysis of the tandem BRCT in Nbs1 supports its function as a phosphoserine binding domain. Remarkably, the 5 bp deletion observed in 95% of NBS patients cleaves the tandem at the linker region while preserving the structural integrity of each BRCT domain in the resulting truncated gene products.

Protein surfaces are under significant selection pressure to maintain interactions with their partners throughout evolution. Capturing how selection pressure acts at the interfaces of proteinprotein complexes is a fundamental issue with high interest for the structural prediction of macromolecular assemblies. We tackled this issue under the assumption that, throughout evolution, mutations should minimally disrupt the physicochemical compatibility between specific clusters of interacting residues. This constraint drove the development of the so-called Surface COmplementarity Trace in Complex History score (SCOTCH), which was found to discriminate with high efficiency the structure of biological complexes. SCOTCH performances were assessed not only with respect to other evolution-based approaches, such as conservation and coevolution analyses, but also with respect to statistically based scoring methods. Validated on a set of 129 complexes of known structure exhibiting both permanent and transient intermolecular interactions, SCOTCH appears as a robust strategy to guide the prediction of protein-protein complex structures. Of particular interest, it also provides a basic framework to efficiently track how protein surfaces could evolve while keeping their partners in contact.evolution ͉ prediction ͉ protein-protein interaction T he modular assembly of proteins is a key determinant in the regulation of biological systems. Combinations of inter-and intramolecular interactions hold the cell machineries and govern the flow of information transmitted through cell signaling pathways. To unravel the complexity of cell organization, atlases of the physical interactome have been obtained for several model organisms (1, 2). To further elucidate the competitions and synergies ruling the molecular logic of these protein-protein interaction networks, a critical step relies on the structural characterization of the protein complexes. However, there is still a huge gap between the proteome-wide data accumulating and the available structural details of macromolecular complexes.A number of studies have tackled the large-scale analysis of protein-protein complexes from a structural perspective (3-7). They have emphasized that size, shape, and the physicochemical complementarities at the interfaces are key descriptors that could be used to develop computational methods able to predict protein-binding sites from sequences or structures (8)(9)(10)(11)(12)(13)(14). In the context of evolution, seminal studies compared the binding modes of domain-domain interactions between homologous proteins and concluded that they tend to interact similarly, even if sequence identity has been maintained as low as 30% (15, 16). Such a low conservation threshold suggests that interaction surfaces can evolve significantly while maintaining sufficient specificity between the binding partners. The paradox between sequence divergence and structural conservation of macromolecular assemblies has been recently related to the notion of superfamily, and the exis...