Biomolecular condensate

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Biomolecular condensates are a class of non-membrane bound organelles and organelle subdomains. As with other organelles, biomolecular condensates are specialized subunits of the cell. Unlike many organelles, biomolecular condensate composition is not controlled by a bounding membrane. Instead they are formed by phase separation of proteins and other biopolymers into a colloidal emulsion or gel-sol, which is determined by the physical chemistry of these polymers. Colloidal behaviour is generated by the clustering, oligomerisation or polymerisation of various biomolecules within the cytosol to drive either liquid-liquid, liquid-gel, or liquid-solid phase separation. Biomolecular condensation is a form of self-assembly or self-organisation and is strongly enhanced by macromolecular crowding.

The concept of biomolecular condensates as an organising principle for the compartmentalisation of living cells dates back to the 19th Century, beginning with William Bate Hardy and Edmund Beecher Wilson describing the cytoplasm (then called 'protoplasm') as a colloid.[1][2] Around the same time, Thomas Harrison Montgomery Jr. described the morphology of the nucleolus, an organelle within the nucleus.[3] More recently, the term phase separation was borrowed from polymer physics and colloidal chemistry to describe the colloidal segregation of the cytoplasm [4] and nucleus.[5] The newly coined term 'biomolecular condensate' selectively refers to biological polymers (as opposed to synthetic polymers) undergoing colloidal phase separation, which is analogous to condensation - a colloidal form of gas-liquid phase transition and subsequent separation.[6][7]

In physics, condensation often means a gas-liquid phase transition, while in biology the term 'condensation' is used much more broadly and can also refer to liquid-liquid, liquid-gel, or liquid-solid phase separation, as well as liquid-to-solid phase transitions such as DNA condensation during prophase of the cell cycle or protein condensation of crystallins in cataracts [8] - hence the use of 'biomolecular condensate' to broadly describe biological colloids of many different types.

Liquid droplets in cells[edit]

The term biomolecular condensate is not universally applied, and some non-membrane bound structures are just referred to as liquid droplets, or referred to as the product of liquid-liquid phase separation (LLPS) [9].[10] These structures look like the analog of oil droplets in water, i.e., of the cytoplasm or nucleoplasm undergoing liquid-liquid phase separation. The two terms biomolecular condensate and intracellular liquid droplet are often interchangeable, although liquid droplets do have to have the properties of a liquid, while biomolecular condensates may also be more solid or gel-like. In that sense biomolecular condensate may be a more general term, while liquid droplets are a sub-class of biomolecular condensate. The terms 'puncta' or 'dots' were also used, particularly in early studies [11][12][13][14] to describe the same type of structures. Droplets of fluorescently-tagged proteins look like bright dots or points (puncta) of light, in a microscope.

One of the first discovered examples of this class of biomolecular condensate were the supramolecular complexes formed by components of the Wnt signalling pathway.[15][16] The Dishevelled (Dsh) protein undergoes clustering in the cytoplasm [11][12] via its DIX domain, which mediates protein polymerisation, and is important for signal transduction.[14] The Dsh protein functions both in planar polarity and Wnt signalling, where it recruits another supramolecular complex (the Axin complex) to Wnt receptors at the plasma membrane.[12][13] The formation of these Dishevelled and Axin containing droplets is conserved across metazoans, including in Drosophila, Xenopus, and human cells.

Another example of liquid droplets in cells are the germline P granules in Caenorhabditis elegans.[10] These granules separate out from the cytoplasm and form droplets, as oil does from water. Both the granules and the surrounding cytoplasm are liquid in the sense that they flow in response to forces, and two of the granules can coalesce when they come in contact. When (some of) the molecules in the granules are studied (via fluorescence recovery after photobleaching), they are found to rapidly turnover in the droplets, meaning that molecules diffuse into and out of the granules, just as expected in a liquid droplet (but not necessarily for droplets of oil in water, or gel-like droplets). The droplets can also grow to be many molecules across (micrometres)[10] Studies of droplets of the Caenorhabditis elegans protein LAF-1 in vitro[17] also show liquid-like behaviour, with an apparent viscosity Pa s. This is about a ten thousand times that of water at room temperature, but it is small enough to enable the LAF-1 droplets to flow like a liquid.

The formation of these droplets is believed to be linked to biological functions.[9][10]

Examples[edit]

Many examples of biomolecular condensates have been characterized in the cytoplasm and the nucleus.

Cytoplasmic biomolecular condensates arising by either liquid-liquid, liquid-gel or liquid-solid phase separation:

It can also be argued that cytoskeletal filaments form by a polymerisation process similar to phase separation, except ordered into filamentous networks instead of amorphous droplets or granules.

As colloidal phase separation involves oligomeric or polymeric interactions between an indefinite number of components, it is generally considered distinct from formation of smaller protein complexes with defined numbers of subunits, such as viral capsids or the proteasome - although both are examples of spontaneous self-assembly or self-organisation.

Nuclear biomolecular condensates:

Other nuclear structures including heterochromatin and DNA condensation in condensed mitosis chromosomes form by mechanisms similar to phase separation, so can also be classified as biomolecular condensates.

References[edit]

  1. ^ Wilson EB (July 1899). "The Structure of the Protoplasm". Science. 10 (237): 33–45. Bibcode:1899Sci....10...33W. doi:10.1126/science.10.237.33. PMID 17829686.
  2. ^ Hardy WB (May 1899). "On The Structure of Cell Protoplasm". Journal of Physiology. 24 (2): 158–210. doi:10.1113/jphysiol.1899.sp000755. PMC 1516635. PMID 16992486.
  3. ^ Montgomery T (1898). "Comparative cytological studies, with especial regard to the morphology of the nucleolus". Journal of Morphology. 15 (1): 265–582. doi:10.1002/jmor.1050150204.
  4. ^ Walter H, Brooks DE (March 1995). "Phase separation in cytoplasm, due to macromolecular crowding, is the basis for microcompartmentation". FEBS Letters. 361 (2–3): 135–139. doi:10.1016/0014-5793(95)00159-7. PMID 7698310.
  5. ^ Iborra-FJ (Apr 2007). "Can visco-elastic phase separation, macromolecular crowding and colloidal physics explain nuclear organisation?". Theor Biol Med Model. 4 (15): 15. doi:10.1186/1742-4682-4-15. PMC 1853075. PMID 17430588.
  6. ^ Wheeler-RJ, Hyman-AA (Nov 2018). "Controlling compartmentalization by non-membrane-bound organelles". PNAS. 26 (373): 4666–4684. doi:10.1098/rstb.2017.0193. PMC 5904305. PMID 29632271.
  7. ^ Banani SF, Lee HO, Hyman AA, Rosen MK (May 2017). "Biomolecular condensates: organizers of cellular biochemistry". Nat Rev Mol Cell Biol. 18 (5): 285–298. doi:10.1038/nrm.2017.7. PMID 28225081.
  8. ^ Benedek GB (1 September 1997). "Cataract as a protein condensation disease: the Proctor Lecture". Invest. Ophthalmol. Vis. Sci. 38 (10): 1911–21. PMID 9331254.
  9. ^ a b Hyman AA, Weber CA, Jülicher F (2014-10-11). "Liquid-liquid phase separation in biology". Annual Review of Cell and Developmental Biology. 30 (1): 39–58. doi:10.1146/annurev-cellbio-100913-013325. PMID 25288112.
  10. ^ a b c d Brangwynne CP, Eckmann CR, Courson DS, Rybarska A, Hoege C, Gharakhani J, et al. (June 2009). "Germline P granules are liquid droplets that localize by controlled dissolution/condensation". Science. 324 (5935): 1729–32. doi:10.1126/science.1172046. PMID 19460965.
  11. ^ a b Yanagawa S, van Leeuwen F, Wodarz A, Klingensmith J, Nusse R (May 1995). "The dishevelled protein is modified by wingless signaling in Drosophila". Genes & Development. 9 (9): 1087–1097. doi:10.1101/gad.9.9.1087. PMID 7744250.
  12. ^ a b c Axelrod JD, Miller JR, Shulman JM, Moon RT, Perrimon N (August 1998). "Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways". Genes & Development. 12 (16): 2610–22. doi:10.1101/gad.12.16.2610. PMID 9716412.
  13. ^ a b Cliffe A, Hamada F, Bienz M (May 2003). "A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling". Current Biology. 13 (11): 960–6. doi:10.1016/S0960-9822(03)00370-1. PMID 12781135.
  14. ^ a b Schwarz-Romond T, Fiedler M, Shibata N, Butler PJ, Kikuchi A, Higuchi Y, Bienz M (June 2007). "The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization". Nature Structural & Molecular Biology. 14 (6): 484–92. doi:10.1038/nsmb1247. PMID 17529994.
  15. ^ Schaefer KN, Peifer M (February 2019). "Wnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates". Developmental Cell. 48 (4): 429–444. doi:10.1016/j.devcel.2019.01.025. PMC 6386181. PMID 30782412.
  16. ^ Gammons M, Bienz M (April 2018). "Multiprotein complexes governing Wnt signal transduction". Current Opinion in Cell Biology. 51 (1): 42–49. doi:10.1016/j.ceb.2017.10.008. PMID 29153704.
  17. ^ Elbaum-Garfinkle S, Kim Y, Szczepaniak K, Chen CC, Eckmann CR, Myong S, Brangwynne CP (June 2015). "The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics". Proceedings of the National Academy of Sciences of the United States of America. 112 (23): 7189–94. doi:10.1073/pnas.1504822112. PMC 4466716. PMID 26015579.
  18. ^ Schaefer KN, Peifer M (Feb 2019). "Wnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates". Developmental Cell. 48 (4): 429–444. doi:10.1016/j.devcel.2019.01.025. PMC 6386181. PMID 30782412.
  19. ^ Gammons M, Bienz M (Apr 2018). "Multiprotein complexes governing Wnt signal transduction". Current Opinion in Cell Biology. 51 (1): 42–49. doi:10.1016/j.ceb.2017.10.008. PMID 29153704.

Further reading[edit]