DIP/Dpr interactions and the evolutionary design of specificity in protein families

Alina P. Sergeeva, Phinikoula S. Katsamba, Filip Cosmanescu, Joshua J. Brewer, Goran Ahlsen, Seetha Mannepalli, Lawrence Shapiro, Barry Honig
2020 Nature Communications  
Differential binding affinities among closely related protein family members underlie many biological phenomena, including cell-cell recognition. Drosophila DIP and Dpr proteins mediate neuronal targeting in the fly through highly specific protein-protein interactions. We show here that DIPs/Dprs segregate into seven specificity subgroups defined by binding preferences between their DIP and Dpr members. We then describe a sequence-, structure- and energy-based computational approach, combined
more » ... th experimental binding affinity measurements, to reveal how specificity is coded on the canonical DIP/Dpr interface. We show that binding specificity of DIP/Dpr subgroups is controlled by "negative constraints", which interfere with binding. To achieve specificity, each subgroup utilizes a different combination of negative constraints, which are broadly distributed and cover the majority of the protein-protein interface. We discuss the structural origins of negative constraints, and potential general implications for the evolutionary origins of binding specificity in multi-protein families.
doi:10.1038/s41467-020-15981-8 pmid:32358559 fatcat:evm66hmjd5c65ljugfszul3plq