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Biomolecular condensates: organizers of cellular biochemistry

Nature Reviews Molecular Cell Biology volume 18, pages 285–298 (2017)Cite this article

Subjects

Key Points

  • In addition to canonical membrane-bound organelles, eukaryotic cells contain numerous membraneless compartments, or biomolecular condensates, that concentrate specific collections of proteins and nucleic acids.

  • Biomolecular condensates behave as phase-separated liquids and are enriched in multivalent molecules.

  • Theoretical concepts from polymer and physical chemistry regarding the behaviour of multivalent molecules provide a mechanistic framework that can explain a wide range of cellular behaviours exhibited by biomolecular condensates, including plausible mechanisms by which their assembly, composition, and biochemical and cellular functions can be regulated.

Abstract

Biomolecular condensates are micron-scale compartments in eukaryotic cells that lack surrounding membranes but function to concentrate proteins and nucleic acids. These condensates are involved in diverse processes, including RNA metabolism, ribosome biogenesis, the DNA damage response and signal transduction. Recent studies have shown that liquid–liquid phase separation driven by multivalent macromolecular interactions is an important organizing principle for biomolecular condensates. With this physical framework, it is now possible to explain how the assembly, composition, physical properties and biochemical and cellular functions of these important structures are regulated.

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Figure 1: Biomolecular condensates in eukaryotic cells.
Figure 2: Different modes of multivalent interactions in synthetic and natural systems undergoing liquid–liquid phase separation.
Figure 3: A model for compositional control of biomolecular condensates.
Figure 4: Changing material properties of biomolecular condensates.
Figure 5: Functional consequences of forming biomolecular condensates.

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Acknowledgements

The authors thank R. Duronio and C. Weber for discussion and critical comments on the Review. Research on multivalency-driven phase separation is supported in the Hyman laboratory by the Max Planck Society, and in the Rosen laboratory by the Howard Hughes Medical Institute, the Welch Foundation (I-1544) and a Sara and Frank McKnight Graduate Fellowship (to S.F.B.).

Author information

Author notes

  1. Salman F. Banani and Hyun O. Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Salman F. Banani & Michael K. Rosen

  2. Max Planck Institute of Molecular Cell Biology and Genetics, 01307, Dresden, Germany

    Hyun O. Lee & Anthony A. Hyman

Authors
  1. Salman F. Banani
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  2. Hyun O. Lee
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Correspondence to Anthony A. Hyman or Michael K. Rosen.

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Supplementary information

Dripping of P granules.

Movie shows syncytial germ cell nuclei covered in P granules in the germ line of a GFP::PGL-1 worm. The germ line has been dissected and squashed. P granules appear to drip off of the nuclei, fuse, and round up. From Brangwynne, C. P. et al. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324, 1729–1732 (2009). Reprinted with permission from AAAS. (MOV 259 kb)

Dynamics of FUS bodies.

Timelapse imaging of stress granules in a live HeLa cell expressing FUS-GFP using high-resolution lightsheet microscopy. Movie courtesy of H. O. Lee and M. Weigert, MPI-CBG, Dresden, Germany. (MOV 28339 kb)

Fusion of stress granules.

Expanded and rendered movie of the same cell in Supplemental movie 2, showing fusion of two stress granules visualized through FUS-GFP. Movie courtesy of H. O. Lee and M. Weigert, MPI-CBG, Dresden, Germany. (AVI 60 kb)

Formation and merging of pNephrin clusters.

Alexa 488-labeled His8-pNephrin was attached to a DOPC supported lipid bilayer doped (1%) with Ni2+-NTA lipids, and Nck and N-WASP were added. Movie shows TIRF images acquired every minute. Initial clusters are small and numerous, but merge over time to make larger structures. Reproduced from Banjade, S. & Rosen, M. K. Phase transitions of multivalent proteins can promote clustering of membrane receptors. eLife 3, e04123 (2014). (AVI 553 kb)

Supplementary information S5 (box)

How are condensed phases different from macromolecular complexes? (PDF 147 kb)

Supplementary information S6 (table)

Various biomolecular condensates and their functions (PDF 156 kb)

PowerPoint slides

Glossary

Cajal bodies

Biomolecular condensates in eukaryotic nuclei containing coilin and survival motor neuron protein (SMN) as well as many factors involved in mRNA splicing. Cajal bodies are thought to have a role in assembling spliceosomal small nuclear ribonucleoproteins.

PML nuclear bodies

Biomolecular condensates in eukaryotic nuclei containing promyelocytic leukaemia (PML), death domain-associated protein (DAXX) and Sp100. PML nuclear bodies are thought to have a role in apoptotic signalling, antiviral defence and transcriptional regulation.

Entropy

A measure of disorder in a given system. Specifically, the number of microstates possible for a given state. Systems tend to approach states that maximize their entropy.

Free energy

The energy available in a thermodynamic system to work. Systems tend to approach states that minimize their free energy.

Stereospecificity

A property of binding reactions whereby the specificity is largely dictated by the complementary geometries of the ligand and receptor molecules.

WW domains

Small (∼5 kDa) modular signalling domains found in numerous proteins that contain two conserved tryptophan residues. WW domains bind to proline-containing peptide motifs.

Cation–pi interactions

Noncovalent interactions between positively charged residues (for example, lysine) and pi electrons in aromatic residues (for example, phenylalanine).

Pi-stacking interactions

Attractive interactions between aromatic rings, such as those found in phenylalanine, tyrosine and tryptophan residues.

Dipolar interactions

Interactions between two molecules that are electrically polarized, wherein the partial positive charge on one interacts with the partial negative charge on the other.

Chemical footprinting

Use of a small reactive chemical to modify solvent-exposed sites in a macromolecule, providing information on the structure of that macromolecule.

Chemical potential

The partial molar free energy within a system. Mathematically, the first derivative of free energy with respect to composition. Systems tend to approach states that dissipate gradients in chemical potential.

Histone locus bodies

Biomolecular condensates in eukaryotic nuclei containing nuclear protein, ataxia-telangiectasia locus (NPAT) and FLICE-associated huge protein (FLASH), and thought to be involved in the processing of histone mRNAs.

Nuage

Biomolecular condensates in metazoan germ cells thought to have a role in maintaining germ cell genomic integrity. This class of compartments includes P granules, polar granules and mammalian nuages.

Paraspeckles

Biomolecular condensates in the mammalian nucleus that contain the long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) and a variety of RNA-binding and other proteins. The functions of paraspeckles are not well understood, but include storage of certain RNAs.

Balbiani bodies

A transient collection of proteins, RNA and membrane-bound organelles (endoplasmic reticulum, Golgi and mitochondria) found in primary oocytes of all animals observed to date (flies, frogs, mice and humans).

Small nuclear ribonucleoprotein

A RNA–protein complex that is the primary constituent of spliceosomes, the eukaryotic splicing machinery.

Hammerhead ribozyme

A catalytic RNA molecule involved in RNA cleavage found in organisms ranging from bacteria to mammals.

Partition coefficients

Measures the enrichment of chemical species into the condensed phase of a two-phase system. Mathematically, the partition coefficient is defined as the ratio of concentration of the species in the condensed phase to that in the dilute phase.

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Banani, S., Lee, H., Hyman, A. et al. Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol 18, 285–298 (2017). https://doi.org/10.1038/nrm.2017.7

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