RT Journal Article
SR Electronic
T1 DIP/Dpr interactions and the evolutionary design of specificity in protein families
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.13.899120
DO 10.1101/2020.01.13.899120
A1 Alina P. Sergeeva
A1 Phinikoula S. Katsamba
A1 Filip Cosmanescu
A1 Joshua J. Brewer
A1 Goran Ahlsen
A1 Seetha Mannepalli
A1 Lawrence Shapiro
A1 Barry Honig
YR 2020
UL http://biorxiv.org/content/early/2020/01/13/2020.01.13.899120.abstract
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.