PT  - JOURNAL ARTICLE
AU  - Alina P. Sergeeva
AU  - Phinikoula S. Katsamba
AU  - Filip Cosmanescu
AU  - Joshua J. Brewer
AU  - Goran Ahlsen
AU  - Seetha Mannepalli
AU  - Lawrence Shapiro
AU  - Barry Honig
TI  - DIP/Dpr interactions and the evolutionary design of specificity in protein families
AID  - 10.1101/2020.01.13.899120
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.13.899120
4099  - http://biorxiv.org/content/early/2020/01/13/2020.01.13.899120.short
4100  - http://biorxiv.org/content/early/2020/01/13/2020.01.13.899120.full
AB  - 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. DIPs/Dprs segregate into seven specificity subgroups defined by binding preferences between their DIP and Dpr members. Here we 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.