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bioRxiv · 10.1101/2020.01.13.899120

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

Sergeeva, A. P.·Katsamba, P. S.·Cosmanescu, F.·Brewer, J. J.·Ahlsen, G.·Mannepalli, S.·Shapiro, L.·Honig, B.
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Abstract

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 novel 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.

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Sergeeva, A. P., Katsamba, P. S., Cosmanescu, F., Brewer, J. J., Ahlsen, G., Mannepalli, S., Shapiro, L., Honig, B.. 2020-01-14. DIP/Dpr interactions and the evolutionary design of specificity in protein families. https://doi.org/10.1101/2020.01.13.899120

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