Predicting disordered regions driving phase separation of proteins under variable salt concentration

被引:2
作者
Meca, Esteban [1 ]
Fritsch, Anatol W. [2 ,3 ]
Iglesias-Artola, Juan M. [2 ]
Reber, Simone [4 ,5 ,6 ]
Wagner, Barbara [7 ]
机构
[1] Univ Cordoba, Dept Fis Aplicada Radiol & Med Fis, Cordoba, Spain
[2] Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany
[3] Ctr Syst Biol Dresden, Dresden, Germany
[4] Humboldt Univ, IRI Life Sci, Berlin, Germany
[5] Max Planck Inst Infect Biol, Berlin, Germany
[6] Univ Appl Sci Berlin, Berlin, Germany
[7] Weierstrass Inst Berlin, Berlin, Germany
关键词
intrinsically disordered proteins (IDP); Random Phase Approximation (RPA); FUS; liquid-liquid phase separation (LLPS); phase diagrams; CHARGED POLYELECTROLYTES; COMPLEX COACERVATION; GRANULES;
D O I
10.3389/fphy.2023.1213304
中图分类号
O4 [物理学];
学科分类号
0702 ;
摘要
We investigate intrinsically disordered regions (IDRs) of phase separating proteins regarding their impact on liquid-liquid phase separation (LLPS) of the full protein. Our theoretical approach uses a mean-field theory that accounts for sequence-dependent electrostatic interactions via a Random Phase Approximation (RPA) and in addition allows for variable salt concentration for the condensed and dilute protein phases. The numerical solution of the complete phase diagrams together with the tie lines that we derive for this model system leaves two parameters to be determined by fitting experimental data on concentrations of all species involved in the system. For our comparisons, we focus on two proteins, PGL-3 and FUS, known to undergo LLPS. For PGL-3 we predict that its long IDR near the C-terminus promotes LLPS, which we validate through direct comparison with in vitro experimental results under the same physiological conditions. For the structurally more complex protein FUS the role of the low complexity (LC) domain in LLPS has been intensively studied. Apart from the LC domain we here investigate theoretically two IDRs, one near the N-terminus and another near the C-terminus. Our theoretical analysis of these domains predict that the IDR at the N-terminus (aa 1-285) is the main driver of LLPS of FUS by comparison to in vitro experiments of the full length protein under the same physiological temperature and salt conditions.
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页数:13
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