Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions

Georg Krainer; Timothy J. Welsh; Jerelle A. Joseph; Jorge R. Espinosa; Sina Wittmann; Ella de Csilléry; Akshay Sridhar; Zenon Toprakcioglu; Giedre Gudiškytė; Magdalena A. Czekalska; William E. Arter; Jordina Guillén-Boixet; Titus M. Franzmann; Seema Qamar; Peter St George-Hyslop; Anthony A. Hyman; Rosana Collepardo-Guevara; Simon Alberti; Tuomas P.J. Knowles

doi:10.1038/s41467-021-21181-9

Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions

Georg Krainer, Timothy J. Welsh, Jerelle A. Joseph, Jorge R. Espinosa, Sina Wittmann, Ella de Csilléry, Akshay Sridhar, Zenon Toprakcioglu, Giedre Gudiškytė, Magdalena A. Czekalska, William E. Arter, Jordina Guillén-Boixet, Titus M. Franzmann, Seema Qamar, Peter St George-Hyslop, Anthony A. Hyman, Rosana Collepardo-Guevara, Simon Alberti, Tuomas P.J. Knowles

Research output: Contribution to journal › Article › peer-review

224 Scopus citations

Abstract

Liquid–liquid phase separation of proteins underpins the formation of membraneless compartments in living cells. Elucidating the molecular driving forces underlying protein phase transitions is therefore a key objective for understanding biological function and malfunction. Here we show that cellular proteins, which form condensates at low salt concentrations, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, can reenter a phase-separated regime at high salt concentrations. By bringing together experiments and simulations, we demonstrate that this reentrant phase transition in the high-salt regime is driven by hydrophobic and non-ionic interactions, and is mechanistically distinct from the low-salt regime, where condensates are additionally stabilized by electrostatic forces. Our work thus sheds light on the cooperation of hydrophobic and non-ionic interactions as general driving forces in the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.

Original language	English (US)
Article number	1085
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21181-9
State	Published - Dec 1 2021
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-021-21181-9

Cite this

Krainer, G., Welsh, T. J., Joseph, J. A., Espinosa, J. R., Wittmann, S., de Csilléry, E., Sridhar, A., Toprakcioglu, Z., Gudiškytė, G., Czekalska, M. A., Arter, W. E., Guillén-Boixet, J., Franzmann, T. M., Qamar, S., George-Hyslop, P. S., Hyman, A. A., Collepardo-Guevara, R., Alberti, S., & Knowles, T. P. J. (2021). Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions. Nature communications, 12(1), Article 1085. https://doi.org/10.1038/s41467-021-21181-9

@article{37a6fd3987934073a415bbc075f869a2,

title = "Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions",

abstract = "Liquid–liquid phase separation of proteins underpins the formation of membraneless compartments in living cells. Elucidating the molecular driving forces underlying protein phase transitions is therefore a key objective for understanding biological function and malfunction. Here we show that cellular proteins, which form condensates at low salt concentrations, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, can reenter a phase-separated regime at high salt concentrations. By bringing together experiments and simulations, we demonstrate that this reentrant phase transition in the high-salt regime is driven by hydrophobic and non-ionic interactions, and is mechanistically distinct from the low-salt regime, where condensates are additionally stabilized by electrostatic forces. Our work thus sheds light on the cooperation of hydrophobic and non-ionic interactions as general driving forces in the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.",

author = "Georg Krainer and Welsh, {Timothy J.} and Joseph, {Jerelle A.} and Espinosa, {Jorge R.} and Sina Wittmann and {de Csill{\'e}ry}, Ella and Akshay Sridhar and Zenon Toprakcioglu and Giedre Gudi{\v s}kytė and Czekalska, {Magdalena A.} and Arter, {William E.} and Jordina Guill{\'e}n-Boixet and Franzmann, {Titus M.} and Seema Qamar and George-Hyslop, {Peter St} and Hyman, {Anthony A.} and Rosana Collepardo-Guevara and Simon Alberti and Knowles, {Tuomas P.J.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-21181-9",

language = "English (US)",

volume = "12",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Krainer, G, Welsh, TJ, Joseph, JA, Espinosa, JR, Wittmann, S, de Csilléry, E, Sridhar, A, Toprakcioglu, Z, Gudiškytė, G, Czekalska, MA, Arter, WE, Guillén-Boixet, J, Franzmann, TM, Qamar, S, George-Hyslop, PS, Hyman, AA, Collepardo-Guevara, R, Alberti, S & Knowles, TPJ 2021, 'Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions', Nature communications, vol. 12, no. 1, 1085. https://doi.org/10.1038/s41467-021-21181-9

TY - JOUR

T1 - Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions

AU - Krainer, Georg

AU - Welsh, Timothy J.

AU - Joseph, Jerelle A.

AU - Espinosa, Jorge R.

AU - Wittmann, Sina

AU - de Csilléry, Ella

AU - Sridhar, Akshay

AU - Toprakcioglu, Zenon

AU - Gudiškytė, Giedre

AU - Czekalska, Magdalena A.

AU - Arter, William E.

AU - Guillén-Boixet, Jordina

AU - Franzmann, Titus M.

AU - Qamar, Seema

AU - George-Hyslop, Peter St

AU - Hyman, Anthony A.

AU - Collepardo-Guevara, Rosana

AU - Alberti, Simon

AU - Knowles, Tuomas P.J.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Liquid–liquid phase separation of proteins underpins the formation of membraneless compartments in living cells. Elucidating the molecular driving forces underlying protein phase transitions is therefore a key objective for understanding biological function and malfunction. Here we show that cellular proteins, which form condensates at low salt concentrations, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, can reenter a phase-separated regime at high salt concentrations. By bringing together experiments and simulations, we demonstrate that this reentrant phase transition in the high-salt regime is driven by hydrophobic and non-ionic interactions, and is mechanistically distinct from the low-salt regime, where condensates are additionally stabilized by electrostatic forces. Our work thus sheds light on the cooperation of hydrophobic and non-ionic interactions as general driving forces in the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.

AB - Liquid–liquid phase separation of proteins underpins the formation of membraneless compartments in living cells. Elucidating the molecular driving forces underlying protein phase transitions is therefore a key objective for understanding biological function and malfunction. Here we show that cellular proteins, which form condensates at low salt concentrations, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, can reenter a phase-separated regime at high salt concentrations. By bringing together experiments and simulations, we demonstrate that this reentrant phase transition in the high-salt regime is driven by hydrophobic and non-ionic interactions, and is mechanistically distinct from the low-salt regime, where condensates are additionally stabilized by electrostatic forces. Our work thus sheds light on the cooperation of hydrophobic and non-ionic interactions as general driving forces in the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.

UR - http://www.scopus.com/inward/record.url?scp=85100820646&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85100820646&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-21181-9

DO - 10.1038/s41467-021-21181-9

M3 - Article

C2 - 33597515

AN - SCOPUS:85100820646

SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1085

ER -

Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this