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Scientific article
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English

A unified statistical potential reveals that amino acid stickiness governs nonspecific recruitment of client proteins into condensates

Published inProtein science, vol. 31, no. 7, e4361
Publication date2022-06-20
First online date2022-06-20
Abstract

Membraneless organelles are cellular compartments that form by liquid–liquid phase separation of one or more components. Other molecules, such as proteins and nucleic acids, will distribute between the cytoplasm and the liquid compartment in accordance with the thermodynamic drive to lower the free energy of the system. The resulting distribution colocalizes molecular species to carry out a diversity of functions. Two factors could drive this partitioning: the difference in solvation between the dilute versus dense phase and intermolecular interactions between the client and scaffold proteins. Here, we develop a set of knowledge‐based potentials that allow for the direct comparison between stickiness, which is dominated by desolvation energy, and pairwise residue contact propensity terms. We use these scales to examine experimental data from two systems: protein cargo dissolving within phase‐separated droplets made from FG repeat proteins of the nuclear pore complex and client proteins dissolving within phase‐separated FUS droplets. These analyses reveal a close agreement between the stickiness of the client proteins and the experimentally determined values of the partition coefficients ( R > 0.9), while pairwise residue contact propensities between client and scaffold show weaker correlations. Hence, the stickiness of client proteins is sufficient to explain their differential partitioning within these two phase‐separated systems without taking into account the composition of the condensate. This result implies that selective trafficking of client proteins to distinct membraneless organelles requires recognition elements beyond the client sequence composition.

Statement

Empirical potentials for amino acid stickiness and pairwise residue contact propensities are derived. These scales are unique in that they enable direct comparison of desolvation versus contact terms. We find that partitioning of a client protein to a condensate is best explained by amino acid stickiness.

eng
Keywords
  • Amino acid stickiness
  • Biomolecular condensates
  • Contact potential
  • Interface propensity
  • Sequence-function relationships
  • Statistical energy
Affiliation Not a UNIGE publication
Funding
  • European Commission - Infinite Protein Self-Assembly in Health and Disease [819318]
  • Israel Science Foundation - [1452/18]
  • NATPE Educational Foundation -
  • Horizon 2020 Framework Programme -
  • European Research Council -
Citation (ISO format)
VILLEGAS, José A., LEVY, Emmanuel. A unified statistical potential reveals that amino acid stickiness governs nonspecific recruitment of client proteins into condensates. In: Protein science, 2022, vol. 31, n° 7, p. e4361. doi: 10.1002/pro.4361
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Article (Published version)
Identifiers
ISSN of the journal0961-8368
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