Direct Prediction of Intermolecular Interactions Driven by Disordered Regions

Overview

Journal bioRxiv

Date 2024 Jun 19

PMID 38895487

Authors

Garrett M Ginell

Ryan J Emenecker

Jeffrey M Lotthammer

Emery T Usher

Alex S Holehouse

Affiliations

Soon will be listed here.

Abstract

Intrinsically disordered regions (IDRs) are critical for a wide variety of cellular functions, many of which involve interactions with partner proteins. Molecular recognition is typically considered through the lens of sequence-specific binding events. However, a growing body of work has shown that IDRs often interact with partners in a manner that does not depend on the precise order of the amino acid order, instead driven by complementary chemical interactions leading to disordered bound-state complexes. Despite this emerging paradigm, we lack tools to describe, quantify, predict, and interpret these types of structurally heterogeneous interactions from the underlying amino acid sequences. Here, we repurpose the chemical physics developed originally for molecular simulations to develop an approach for predicting intermolecular interactions between IDRs and partner proteins. Our approach enables the direct prediction of phase diagrams, the identification of chemically-specific interaction hotspots on IDRs, and a route to develop and test mechanistic hypotheses regarding IDR function in the context of molecular recognition. We use our approach to examine a range of systems and questions to highlight its versatility and applicability.

References

Lund M, Jonsson B . Charge regulation in biomolecular solution. Q Rev Biophys. 2013; 46(3):265-81. DOI: 10.1017/S003358351300005X. View

Olsen J, Teilum K, Kragelund B . Behaviour of intrinsically disordered proteins in protein-protein complexes with an emphasis on fuzziness. Cell Mol Life Sci. 2017; 74(17):3175-3183. PMC: 5533869. DOI: 10.1007/s00018-017-2560-7. View

Han T, Kato M, Xie S, Wu L, Mirzaei H, Pei J . Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell. 2012; 149(4):768-79. DOI: 10.1016/j.cell.2012.04.016. View

Wills P, Scott D, Winzor D . The osmotic second virial coefficient for protein self-interaction: Use and misuse to describe thermodynamic nonideality. Anal Biochem. 2015; 490:55-65. DOI: 10.1016/j.ab.2015.08.020. View

Tompa P, Fuxreiter M . Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci. 2007; 33(1):2-8. DOI: 10.1016/j.tibs.2007.10.003. View

Sharma R, Raduly Z, Miskei M, Fuxreiter M . Fuzzy complexes: Specific binding without complete folding. FEBS Lett. 2015; 589(19 Pt A):2533-42. DOI: 10.1016/j.febslet.2015.07.022. View

Lu A, Lu A, Pritisanac I, Zarin T, Forman-Kay J, Moses A . Discovering molecular features of intrinsically disordered regions by using evolution for contrastive learning. PLoS Comput Biol. 2022; 18(6):e1010238. PMC: 9275697. DOI: 10.1371/journal.pcbi.1010238. View

Staller M, Holehouse A, Swain-Lenz D, Das R, Pappu R, Cohen B . A High-Throughput Mutational Scan of an Intrinsically Disordered Acidic Transcriptional Activation Domain. Cell Syst. 2018; 6(4):444-455.e6. PMC: 5920710. DOI: 10.1016/j.cels.2018.01.015. View

Chao J, Parganas E, Boyd K, Hong C, Opferman J, Ihle J . Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature. 2008; 452(7183):98-102. DOI: 10.1038/nature06604. View

10.

Conicella A, Zerze G, Mittal J, Fawzi N . ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain. Structure. 2016; 24(9):1537-49. PMC: 5014597. DOI: 10.1016/j.str.2016.07.007. View

11.

Bremer A, Farag M, Borcherds W, Peran I, Martin E, Pappu R . Deciphering how naturally occurring sequence features impact the phase behaviours of disordered prion-like domains. Nat Chem. 2021; 14(2):196-207. PMC: 8818026. DOI: 10.1038/s41557-021-00840-w. View

12.

Crabtree M, Holland J, Pillai A, Kompella P, Babl L, Turner N . Ion binding with charge inversion combined with screening modulates DEAD box helicase phase transitions. Cell Rep. 2023; 42(11):113375. PMC: 10935546. DOI: 10.1016/j.celrep.2023.113375. View

13.

Burke K, Janke A, Rhine C, Fawzi N . Residue-by-Residue View of In Vitro FUS Granules that Bind the C-Terminal Domain of RNA Polymerase II. Mol Cell. 2015; 60(2):231-41. PMC: 4609301. DOI: 10.1016/j.molcel.2015.09.006. View

14.

Rekhi S, Garcia C, Barai M, Rizuan A, Schuster B, Kiick K . Expanding the molecular language of protein liquid-liquid phase separation. Nat Chem. 2024; 16(7):1113-1124. PMC: 11230844. DOI: 10.1038/s41557-024-01489-x. View

15.

Hein M, Hubner N, Poser I, Cox J, Nagaraj N, Toyoda Y . A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell. 2015; 163(3):712-23. DOI: 10.1016/j.cell.2015.09.053. View

16.

Wadsworth G, Zahurancik W, Zeng X, Pullara P, Lai L, Sidharthan V . RNAs undergo phase transitions with lower critical solution temperatures. Nat Chem. 2023; 15(12):1693-1704. PMC: 10872781. DOI: 10.1038/s41557-023-01353-4. View

17.

Nott T, Petsalaki E, Farber P, Jervis D, Fussner E, Plochowietz A . Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol Cell. 2015; 57(5):936-947. PMC: 4352761. DOI: 10.1016/j.molcel.2015.01.013. View

18.

Gruijs da Silva L, Simonetti F, Hutten S, Riemenschneider H, Sternburg E, Pietrek L . Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation. EMBO J. 2022; 41(8):e108443. PMC: 9016352. DOI: 10.15252/embj.2021108443. View

19.

Shinn M, Cohan M, Bullock J, Ruff K, Levin P, Pappu R . Connecting sequence features within the disordered C-terminal linker of FtsZ to functions and bacterial cell division. Proc Natl Acad Sci U S A. 2022; 119(42):e2211178119. PMC: 9586301. DOI: 10.1073/pnas.2211178119. View

20.

Joseph J, Reinhardt A, Aguirre A, Chew P, Russell K, Espinosa J . Physics-driven coarse-grained model for biomolecular phase separation with near-quantitative accuracy. Nat Comput Sci. 2022; 1(11):732-743. PMC: 7612994. DOI: 10.1038/s43588-021-00155-3. View