Abstract
Protein phase separation is implicated in formation of membraneless organelles, signaling puncta and the nuclear pore. Multivalent interactions of modular binding domains and their target motifs can drive phase separation. However, forces promoting the more common phase separation of intrinsically disordered regions are less understood, with suggested roles for multivalent cation-pi, pi-pi, and charge interactions and the hydrophobic effect. Known phase-separating proteins are enriched in pi-orbital containing residues and thus we analyzed pi-interactions in folded proteins. We found that pi-pi interactions involving non-aromatic groups are widespread, underestimated by force-fields used in structure calculations and correlated with solvation and lack of regular secondary structure, properties associated with disordered regions. We present a phase separation predictive algorithm based on pi interaction frequency, highlighting proteins involved in biomaterials and RNA processing.
Highlights
Protein phase separation has important implications for cellular organization and signaling (Mitrea and Kriwacki, 2016; Brangwynne et al, 2009; Su et al, 2016), RNA processing (Sfakianos et al, 2016), biological materials (Yeo et al, 2011) and pathological aggregation (Taylor et al, 2016)
We searched the protein data bank (PDB) for pipi interactions by measuring contact distances between planar surfaces and comparing planar orientations, choosing to focus on interactions involving pi-orbital planar surfaces as this category shows the most enrichment over expectations, both in terms of overall frequency (Appendix 1—figure 1) and in relation to resolution
28% of heavy atoms that are not directly involved in pi-stacking are found within van der Waals (VDW) contact distance (4.9 A ) of Figure 1 continued on page
Summary
Protein phase separation has important implications for cellular organization and signaling (Mitrea and Kriwacki, 2016; Brangwynne et al, 2009; Su et al, 2016), RNA processing (Sfakianos et al, 2016), biological materials (Yeo et al, 2011) and pathological aggregation (Taylor et al, 2016). The underlying physical principles and chemical interactions that drive phase separation in these IDRs are not well understood. Multivalent (Li et al, 2012; Pierce et al, 2016) electrostatic (Pak et al, 2016; Lin et al, 2016) and cation-pi (Nott et al, 2015; Kim et al, 2016; Sherrill, 2013) interactions and the hydrophobic effect (Yeo et al, 2011) have all been proposed to contribute to IDR phase separation, the latter suggested to be dominant for tropoelastin (Luan et al, 1990). A number of physical interactions may be sufficient for driving phase
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