DIP/Dpr Interactions and the Evolutionary Design of Specificity in Protein Families

Overview

Journal Nat Commun

Specialty Biology

Date 2020 May 3

PMID 32358559

Citations 18

Authors

Alina P Sergeeva

Phinikoula S Katsamba

Filip Cosmanescu

Joshua J Brewer

Goran Ahlsen

Seetha Mannepalli

Lawrence Shapiro

Barry Honig

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Gradients of Recognition Molecules Shape Synaptic Specificity of Visuomotor Transformation.

Dombrovski M, Zang Y, Frighetto G, Vaccari A, Jang H, Mirshahidi P bioRxiv. 2025; .

PMID: 39974884 PMC: 11838220. DOI: 10.1101/2024.09.04.610846.

Following the Evolutionary Paths of Dscam1 Proteins toward Highly Specific Homophilic Interactions.

Wiseglass G, Rubinstein R Mol Biol Evol. 2024; 41(7).

PMID: 38989909 PMC: 11272049. DOI: 10.1093/molbev/msae141.

Robust Prediction of Relative Binding Energies for Protein-Protein Complex Mutations Using Free Energy Perturbation Calculations.

Sampson J, Cannon D, Duan J, Epstein J, Sergeeva A, Katsamba P J Mol Biol. 2024; 436(16):168640.

PMID: 38844044 PMC: 11339910. DOI: 10.1016/j.jmb.2024.168640.

Robust prediction of relative binding energies for protein-protein complex mutations using free energy perturbation calculations.

Sampson J, Cannon D, Duan J, Epstein J, Sergeeva A, Katsamba P bioRxiv. 2024; .

PMID: 38712280 PMC: 11071377. DOI: 10.1101/2024.04.22.590325.

hkb is required for DIP-α expression and target recognition in the Drosophila neuromuscular circuit.

Wang Y, Salazar R, Simonetta L, Sorrentino V, Gatton T, Wu B Commun Biol. 2024; 7(1):507.

PMID: 38678127 PMC: 11055905. DOI: 10.1038/s42003-024-06184-8.

References

Zipursky S, Wojtowicz W, Hattori D . Got diversity? Wiring the fly brain with Dscam. Trends Biochem Sci. 2006; 31(10):581-8. DOI: 10.1016/j.tibs.2006.08.003. View

Wojtowicz W, Wu W, Andre I, Qian B, Baker D, Zipursky S . A vast repertoire of Dscam binding specificities arises from modular interactions of variable Ig domains. Cell. 2007; 130(6):1134-45. PMC: 2707357. DOI: 10.1016/j.cell.2007.08.026. View

Aye Thu C, Chen W, Rubinstein R, Chevee M, Wolcott H, Felsovalyi K . Single-cell identity generated by combinatorial homophilic interactions between α, β, and γ protocadherins. Cell. 2014; 158(5):1045-1059. PMC: 4183217. DOI: 10.1016/j.cell.2014.07.012. View

Schreiner D, Weiner J . Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion. Proc Natl Acad Sci U S A. 2010; 107(33):14893-8. PMC: 2930437. DOI: 10.1073/pnas.1004526107. View

Brasch J, Katsamba P, Harrison O, Ahlsen G, Troyanovsky R, Indra I . Homophilic and Heterophilic Interactions of Type II Cadherins Identify Specificity Groups Underlying Cell-Adhesive Behavior. Cell Rep. 2018; 23(6):1840-1852. PMC: 6029887. DOI: 10.1016/j.celrep.2018.04.012. View

Katsamba P, Carroll K, Ahlsen G, Bahna F, Vendome J, Posy S . Linking molecular affinity and cellular specificity in cadherin-mediated adhesion. Proc Natl Acad Sci U S A. 2009; 106(28):11594-9. PMC: 2710653. DOI: 10.1073/pnas.0905349106. View

Vendome J, Felsovalyi K, Song H, Yang Z, Jin X, Brasch J . Structural and energetic determinants of adhesive binding specificity in type I cadherins. Proc Natl Acad Sci U S A. 2014; 111(40):E4175-84. PMC: 4210030. DOI: 10.1073/pnas.1416737111. View

Harrison O, Vendome J, Brasch J, Jin X, Hong S, Katsamba P . Nectin ectodomain structures reveal a canonical adhesive interface. Nat Struct Mol Biol. 2012; 19(9):906-15. PMC: 3443293. DOI: 10.1038/nsmb.2366. View

Carrillo R, Ozkan E, Menon K, Nagarkar-Jaiswal S, Lee P, Jeon M . Control of Synaptic Connectivity by a Network of Drosophila IgSF Cell Surface Proteins. Cell. 2015; 163(7):1770-1782. PMC: 4720259. DOI: 10.1016/j.cell.2015.11.022. View

10.

Cheng S, Ashley J, Kurleto J, Lobb-Rabe M, Park Y, Carrillo R . Molecular basis of synaptic specificity by immunoglobulin superfamily receptors in . Elife. 2019; 8. PMC: 6374074. DOI: 10.7554/eLife.41028. View

11.

Tan L, Zhang K, Pecot M, Nagarkar-Jaiswal S, Lee P, Takemura S . Ig Superfamily Ligand and Receptor Pairs Expressed in Synaptic Partners in Drosophila. Cell. 2015; 163(7):1756-69. PMC: 4804707. DOI: 10.1016/j.cell.2015.11.021. View

12.

Ozkan E, Carrillo R, Eastman C, Weiszmann R, Waghray D, Johnson K . An extracellular interactome of immunoglobulin and LRR proteins reveals receptor-ligand networks. Cell. 2013; 154(1):228-39. PMC: 3756661. DOI: 10.1016/j.cell.2013.06.006. View

13.

Havranek J, Harbury P . Automated design of specificity in molecular recognition. Nat Struct Biol. 2002; 10(1):45-52. DOI: 10.1038/nsb877. View

14.

Humphris E, Kortemme T . Design of multi-specificity in protein interfaces. PLoS Comput Biol. 2007; 3(8):e164. PMC: 1950952. DOI: 10.1371/journal.pcbi.0030164. View

15.

Leaver-Fay A, Froning K, Atwell S, Aldaz H, Pustilnik A, Lu F . Computationally Designed Bispecific Antibodies using Negative State Repertoires. Structure. 2016; 24(4):641-651. PMC: 4866497. DOI: 10.1016/j.str.2016.02.013. View

16.

Mandell D, Kortemme T . Computer-aided design of functional protein interactions. Nat Chem Biol. 2009; 5(11):797-807. DOI: 10.1038/nchembio.251. View

17.

Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L . The FoldX web server: an online force field. Nucleic Acids Res. 2005; 33(Web Server issue):W382-8. PMC: 1160148. DOI: 10.1093/nar/gki387. View

18.

Grigoryan G, Reinke A, Keating A . Design of protein-interaction specificity gives selective bZIP-binding peptides. Nature. 2009; 458(7240):859-64. PMC: 2748673. DOI: 10.1038/nature07885. View

19.

Capra J, Singh M . Characterization and prediction of residues determining protein functional specificity. Bioinformatics. 2008; 24(13):1473-80. PMC: 2718669. DOI: 10.1093/bioinformatics/btn214. View

20.

Kalinina O, Mironov A, Gelfand M, Rakhmaninova A . Automated selection of positions determining functional specificity of proteins by comparative analysis of orthologous groups in protein families. Protein Sci. 2004; 13(2):443-56. PMC: 2286703. DOI: 10.1110/ps.03191704. View