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Pincus blob elasticity in an intrinsically disordered protein

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A Correction to this article was published on 08 December 2023

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Abstract

Understanding the dynamic structure of intrinsically disordered proteins (IDPs) is important to deciphering their biological functions. Here, we exploit precision entropic elasticity measurements to infer the conformational behavior of a model IDP construct formed from the disordered tail of the neurofilament low molecular weight protein. The IDP construct notably displays a low-force power-law elastic regime, consistent with the Pincus blob model, which allows direct extraction of the Flory exponent, \(\nu \), from the force–extension relationship. We find \(\nu \) increases with added denaturant, transitioning from a nearly ideal chain to a swollen chain in a manner quantitatively consistent with measurements of IDP dimensions from other experimental techniques. We suggest that measurements of entropic elasticity could be broadly useful in the study of IDP structure.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Notes

  1. We dedicate this article to Fyl Pincus as a way to thank him for the friendship, mentorship, and insight he has shared with OS and RB over the years. Further, as demonstrated by the work presented in this article, we note that his “Pincus blob” model is a powerful concept which continues to find applications 47 years after he introduced it.

References

  1. R. Van Der Lee, M. Buljan, B. Lang, R.J. Weatheritt, G.W. Daughdrill, A.K. Dunker, M. Fuxreiter, J. Gough, J. Gsponer, D.T. Jones et al., Classification of intrinsically disordered regions and proteins. Chem. Rev. 114(13), 6589–6631 (2014)

    Article  Google Scholar 

  2. V.N. Uversky, C.J. Oldfield, A.K. Dunker, Intrinsically disordered proteins in human diseases: introducing the d2 concept. Annu. Rev. Biophys. 37, 215–246 (2008)

    Article  Google Scholar 

  3. P.E. Wright, H.J. Dyson, Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J. Mol. Biol. 293(2), 321–331 (1999)

    Article  Google Scholar 

  4. S.-H. Chong, S. Ham, Folding free energy landscape of ordered and intrinsically disordered proteins. Sci. Rep. 9(1), 14927 (2019)

    Article  ADS  Google Scholar 

  5. G.A. Papoian, Proteins with weakly funneled energy landscapes challenge the classical structure-function paradigm. Proc. Natl. Acad. Sci. 105(38), 14237–14238 (2008)

    Article  ADS  Google Scholar 

  6. J.A. Marsh, J.D. Forman-Kay, Sequence determinants of compaction in intrinsically disordered proteins. Biophys. J. 98(10), 2383–2390 (2010)

    Article  ADS  Google Scholar 

  7. H. Hofmann, A. Soranno, A. Borgia, K. Gast, D. Nettels, B. Schuler, Polymer scaling laws of unfolded and intrinsically disordered proteins quantified with single-molecule spectroscopy. Proc. Natl. Acad. Sci. 109(40), 16155–16160 (2012)

    Article  ADS  Google Scholar 

  8. B. Schuler, A. Soranno, H. Hofmann, D. Nettels, Single-molecule fret spectroscopy and the polymer physics of unfolded and intrinsically disordered proteins. Annu. Rev. Biophys. 45, 207–231 (2016)

    Article  Google Scholar 

  9. P. Bernado, D.I. Svergun, Structural analysis of intrinsically disordered proteins by small-angle x-ray scattering. Mol. BioSyst. 8(1), 151–167 (2012)

    Article  Google Scholar 

  10. H. Maity, L. Baidya, G. Reddy, Salt-induced transitions in the conformational ensembles of intrinsically disordered proteins. J. Phys. Chem. B 126(32), 5959–5971 (2022)

    Article  Google Scholar 

  11. J.A. Riback, M.A. Bowman, A.M. Zmyslowski, C.R. Knoverek, J.M. Jumper, J.R. Hinshaw, E.B. Kaye, K.F. Freed, P.L. Clark, T.R. Sosnick, Innovative scattering analysis shows that hydrophobic disordered proteins are expanded in water. Science 358(6360), 238–241 (2017)

    Article  ADS  Google Scholar 

  12. G. Fuertes, N. Banterle, K.M. Ruff, A. Chowdhury, D. Mercadante, C. Koehler, M. Kachala, G. Estrada Girona, S. Milles, A. Mishra et al., Decoupling of size and shape fluctuations in heteropolymeric sequences reconciles discrepancies in saxs vs. fret measurements. Proc. Natl. Acad. Sci. 114(31), 6342–6351 (2017)

  13. J. Song, G.-N. Gomes, T. Shi, C.C. Gradinaru, H.S. Chan, Conformational heterogeneity and fret data interpretation for dimensions of unfolded proteins. Biophys. J. 113(5), 1012–1024 (2017)

    Article  ADS  Google Scholar 

  14. U. Baul, D. Chakraborty, M.L. Mugnai, J.E. Straub, D. Thirumalai, Sequence effects on size, shape, and structural heterogeneity in intrinsically disordered proteins. J. Phys. Chem. B 123(16), 3462–3474 (2019)

    Article  Google Scholar 

  15. I.L. Morgan, R. Avinery, G. Rahamim, R. Beck, O.A. Saleh, Glassy dynamics and memory effects in an intrinsically disordered protein construct. Phys. Rev. Lett. 125(5), 058001 (2020)

    Article  ADS  Google Scholar 

  16. M. Kornreich, E. Malka-Gibor, B. Zuker, A. Laser-Azogui, R. Beck, Neurofilaments function as shock absorbers: compression response arising from disordered proteins. Phys. Rev. Lett. 117(14), 148101 (2016)

    Article  ADS  Google Scholar 

  17. G. Koren, S. Meir, L. Holschuh, H.D. Mertens, T. Ehm, N. Yahalom, A. Golombek, T. Schwartz, D.I. Svergun, O.A. Saleh et al., Intramolecular structural heterogeneity altered by long-range contacts in an intrinsically disordered protein. Proc. Natl. Acad. Sci. 120(30), e2220180120 (2023)

    Article  Google Scholar 

  18. W. Zheng, G. Dignon, M. Brown, Y.C. Kim, J. Mittal, Hydropathy patterning complements charge patterning to describe conformational preferences of disordered proteins. J. Phys. Chem. Lett. 11(9), 3408–3415 (2020)

    Article  Google Scholar 

  19. J.F. Marko, E.D. Siggia, Stretching DNA. Macromolecules 28(26), 8759–8770 (1995)

    Article  ADS  Google Scholar 

  20. A. Solanki, K. Neupane, M.T. Woodside, Single-molecule force spectroscopy of rapidly fluctuating, marginally stable structures in the intrinsically disordered protein \(\alpha \)-synuclein. Phys. Rev. Lett. 112(15), 158103 (2014)

    Article  ADS  Google Scholar 

  21. R. Schwarzl, S. Liese, F.N. Brünig, F. Laudisio, R.R. Netz, Force response of polypeptide chains from water-explicit md simulations. Macromolecules 53(12), 4618–4629 (2020)

    Article  ADS  Google Scholar 

  22. S. Liese, M. Gensler, S. Krysiak, R. Schwarzl, A. Achazi, B. Paulus, T. Hugel, J.P. Rabe, R.R. Netz, Hydration effects turn a highly stretched polymer from an entropic into an energetic spring. ACS Nano 11(1), 702–712 (2017)

    Article  Google Scholar 

  23. P. Pincus, Excluded volume effects and stretched polymer chains. Macromolecules 9(3), 386–388 (1976)

    Article  ADS  Google Scholar 

  24. D.B. McIntosh, G. Duggan, Q. Gouil, O.A. Saleh, Sequence-dependent elasticity and electrostatics of single-stranded DNA: signatures of base-stacking. Biophys. J. 106(3), 659–666 (2014)

    Article  ADS  Google Scholar 

  25. O.A. Saleh, D. McIntosh, P. Pincus, N. Ribeck, Nonlinear low-force elasticity of single-stranded DNA molecules. Phys. Rev. Lett. 102(6), 068301 (2009)

    Article  ADS  Google Scholar 

  26. J.P. Berezney, O.A. Saleh, Electrostatic effects on the conformation and elasticity of hyaluronic acid, a moderately flexible polyelectrolyte. Macromolecules 50(3), 1085–1089 (2017)

    Article  ADS  Google Scholar 

  27. O.A. Saleh, Perspective: Single polymer mechanics across the force regimes. J. Chem. Phys. 142(19), 194902 (2015)

    Article  ADS  Google Scholar 

  28. R. Beck, J. Deek, J.B. Jones, C.R. Safinya, Gel-expanded to gel-condensed transition in neurofilament networks revealed by direct force measurements. Nat. Mater. 9(1), 40–46 (2010)

    Article  ADS  Google Scholar 

  29. A. Laser-Azogui, M. Kornreich, E. Malka-Gibor, R. Beck, Neurofilament assembly and function during neuronal development. Curr. Opin. Cell Biol. 32, 92–101 (2015)

    Article  Google Scholar 

  30. M. Kornreich, R. Avinery, E. Malka-Gibor, A. Laser-Azogui, R. Beck, Order and disorder in intermediate filament proteins. FEBS Lett. 589(19), 2464–2476 (2015)

    Article  Google Scholar 

  31. N. Ribeck, O.A. Saleh, Multiplexed single-molecule measurements with magnetic tweezers. Rev. Sci. Instrum. 79(9), 094301 (2008)

    Article  ADS  Google Scholar 

  32. I.L. Morgan, O.A. Saleh, Tweezepy: A python package for calibrating forces in single-molecule video-tracking experiments. PLoS ONE 16(12), 0262028 (2021)

    Article  Google Scholar 

  33. C. Bouchiat, M.D. Wang, J.-F. Allemand, T. Strick, S. Block, V. Croquette, Estimating the persistence length of a worm-like chain molecule from force-extension measurements. Biophys. J. 76(1), 409–413 (1999)

  34. M. Buscaglia, L.J. Lapidus, W.A. Eaton, J. Hofrichter, Effects of denaturants on the dynamics of loop formation in polypeptides. Biophys. J. 91(1), 276–288 (2006)

    Article  ADS  Google Scholar 

  35. A. Bustamante, J. Sotelo-Campos, D.G. Guerra, M. Floor, C.A.M. Wilson, C. Bustamante, M. Báez, The energy cost of polypeptide knot formation and its folding consequences. Nat. Commun. 8(1), 1581 (2017)

    Article  ADS  Google Scholar 

  36. V.R. Singh, L.J. Lapidus, The intrinsic stiffness of polyglutamine peptides. J. Phys. Chem. B 112(42), 13172–13176 (2008)

    Article  Google Scholar 

  37. A.F. Chin, D. Toptygin, W.A. Elam, T.P. Schrank, V.J. Hilser, Phosphorylation increases persistence length and end-to-end distance of a segment of tau protein. Biophys. J. 110(2), 362–371 (2016)

    Article  ADS  Google Scholar 

  38. V.R. Singh, M. Kopka, Y. Chen, W.J. Wedemeyer, L.J. Lapidus, Dynamic similarity of the unfolded states of proteins l and g. Biochemistry 46(35), 10046–10054 (2007)

    Article  Google Scholar 

  39. H. Schwalbe, K.M. Fiebig, M. Buck, J.A. Jones, S.B. Grimshaw, A. Spencer, S.J. Glaser, L.J. Smith, C.M. Dobson, Structural and dynamical properties of a denatured protein. heteronuclear 3d NMR experiments and theoretical simulations of lysozyme in 8 m urea. Biochemistry 36(29), 8977–8991 (1997)

  40. G. Damaschun, H. Damaschun, K. Gast, C. Gernat, D. Zirwer, Acid denatured apo-cytochrome c is a random coil: Evidence from small-angle x-ray scattering and dynamic light scattering. Biochimica et Biophysica Acta (BBA) - Protein Struct. Mol. Enzymol. 1078(2), 289–295 (1991)

  41. E.P. O’Brien, R.I. Dima, B. Brooks, D. Thirumalai, Interactions between hydrophobic and ionic solutes in aqueous guanidinium chloride and urea solutions: lessons for protein denaturation mechanism. J. Am. Chem. Soc. 129(23), 7346–7353 (2007)

    Article  Google Scholar 

  42. S. Müller-Späth, A. Soranno, V. Hirschfeld, H. Hofmann, S. Rüegger, L. Reymond, D. Nettels, B. Schuler, Charge interactions can dominate the dimensions of intrinsically disordered proteins. Proc. Natl. Acad. Sci. 107(33), 14609–14614 (2010)

    Article  ADS  Google Scholar 

  43. G. Morrison, C. Hyeon, N.M. Toan, B.-Y. Ha, D. Thirumalai, Stretching homopolymers. Macromolecules 40(20), 7343–7353 (2007)

    Article  ADS  Google Scholar 

  44. A. Borgia, W. Zheng, K. Buholzer, M.B. Borgia, A. Schüler, H. Hofmann, A. Soranno, D. Nettels, K. Gast, A. Grishaev et al., Consistent view of polypeptide chain expansion in chemical denaturants from multiple experimental methods. J. Am. Chem. Soc. 138(36), 11714–11726 (2016)

    Article  Google Scholar 

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Acknowledgements

This work was supported by the National Science Foundation under Award No. MCB-2113302 and by the United States-Israel Bi-national Science Foundation under Grant No. 2020787. The authors have no relevant financial or nonfinancial interests to disclose.

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Authors

Contributions

OAS and RB conceived the project. GK and RA synthesized the NFLt construct. HPT conducted single-molecule experiments and performed data analysis. HPT and OAS drafted the manuscript, with assistance and commentary from GK and RB.

Corresponding author

Correspondence to Omar A. Saleh.

Additional information

The original online version of this article was revised: This article was updated to include a co-author: Ian L. Morgan, who is omitted in the initial version due to an oversight. The original article has been corrected.

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Truong, H.P., Morgan, I.L., Koren, G. et al. Pincus blob elasticity in an intrinsically disordered protein. Eur. Phys. J. E 46, 100 (2023). https://doi.org/10.1140/epje/s10189-023-00360-0

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