Sergeeva, A.P., Katsamba, P.S., Cosmanescu, F., Brewer, J.J., Ahlsen, G., Mannepalli, S., Shapiro, L., Honig, B. (2020). DIP/Dpr interactions and the evolutionary design of specificity in protein families.  Nat. Commun. 11(1): 2125.

FBrf0245556

Research paper

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 with 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.

PMC7195491 (PMC) (EuropePMC)