Protein-protein binding selectivity and network topology constrain global and local properties of interface binding networks

Abstract

Protein-protein interactions networks (PPINs) are known to share a highly conserved structure across all organisms. What is poorly understood, however, is the structure of the child interface interaction networks (IINs), which map the binding sites proteins use for each interaction. In this study we analyze four independently constructed IINs from yeast and humans and find a conserved structure of these networks with a unique topology distinct from the parent PPIN. Using an IIN sampling algorithm and a fitness function trained on the manually curated PPINs, we show that IIN topology can be mostly explained as a balance between limits on interface diversity and a need for physico-chemical binding complementarity. This complementarity must be optimized both for functional interactions and against mis-interactions, and this selectivity is encoded in the IIN motifs. To test whether the parent PPIN shapes IINs, we compared optimal IINs in biological PPINs versus random PPINs. We found that the hubs in biological networks allow for selective binding with minimal interfaces, suggesting that binding specificity is an additional pressure for a scale-free-like PPIN. We confirm through phylogenetic analysis that hub interfaces are strongly conserved and rewiring of interactions between proteins involved in endocytosis preserves interface binding selectivity.

Stoichiometric balance of protein copy numbers is measurable and functionally significant in a protein-protein interaction network for yeast endocytosis

“…Thus, to establish stoichiometric balance in a PPIN the binding interfaces must be known. In previous work we analyzed several interface-resolved PPINs, including the 56-protein clathrin-mediated endocytosis (CME) network in yeast [ 20 , 41 ] ( Fig 1A ), and the 127-protein ErbB signaling network in human cells[ 16 ].…”

“…the same interface is used to bind two different partners–the protein’s abundance must equal the sum of that of its partners to have no leftovers ( Fig 2 ). Classic protein-protein interactions networks (PPINs) lack this resolution, but recent studies have begun to add this information, creating what we refer to as interface-interaction networks (IINs)[ 16 , 20 , 41 ]. An IIN tracks not just protein partners but also the binding sites that proteins use to bind.…”

“…In the first part, we define a metric for quantifying stoichiometric balance and how noise in protein expression levels can be approximately accounted for. We apply our algorithm SBOPN to the CME PPIN [ 20 , 41 ] and the ErbB PPIN [ 16 ], highlighting which proteins are over- and underexpressed relative to perfect balance. Although this analysis excludes temporal expression and binding affinity, it provides a starting point for the analysis of these features in the subsequent parts.…”

Building protein-protein interaction networks for Leishmania species through protein structural information

“…The preferential attachment phenomenon is extremely important for the evolutionary process of biological networks, since this process is resulting from the presence of highly conserved domains in hub proteins, and it is related to the free-scale behavior of the networks [ 102 , 104 ]. The high degree of connectivity makes hub proteins essential for network maintenance, presenting a lethal phenotype upon removal of the protein [ 105 ].…”

Hot-spot analysis for drug discovery targeting protein-protein interactions

“…Computational tools can be used to analyze the properties of these disease networks (hubs, connectivity, topology, etc.) [20] and help to highlight the key players that drive most of the characterized diseases [21]. This holds promises for helping to find treatments to revert altered disease networks back to the normal state.…”