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Assemblages: functional units formed by cellular phase separation.

Toretsky JA, Wright PE - J. Cell Biol. (2014)

Bottom Line: The partitioning of intracellular space beyond membrane-bound organelles can be achieved with collections of proteins that are multivalent or contain low-complexity, intrinsically disordered regions.These proteins can undergo a physical phase change to form functional granules or other entities within the cytoplasm or nucleoplasm that collectively we term "assemblage." Intrinsically disordered proteins (IDPs) play an important role in forming a subset of cellular assemblages by promoting phase separation.Recent work points to an involvement of assemblages in disease states, indicating that intrinsic disorder and phase transitions should be considered in the development of therapeutics.

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Affiliation: Department of Oncology, Georgetown University, Washington, DC 20057 jat42@georgetown.edu.

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DNA acts as a scaffold for EWS-FLI1 binding to GGAA repeats, leading to a putative phase transition based upon high concentration of EWS domains. A series of panels (A–D) shows sequential binding of EWS-FLI1 (purple with helical region) to GGAA (red/green) repeats in the DNA. The high concentration of EWS domains that would occur as a result of multiple EWS-FLI1 proteins binding in a DNA microsatellite could lead to a phase transition based upon the intrinsically disordered low-complexity repeats. (E) The increased local concentration of these EWS domain subunits have emergent properties, at a critical concentration depicted here as five proteins, because of a phase transition leading to the sequestration of RNA (cyan). The assemblage and its interaction with RNA could be part of the transcriptional or posttranscriptional machinery. The capture of RNA could tether this dynamic phase separated assemblage to the nascent pre-mRNA or to the posttranscriptional splicing complex.
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fig3: DNA acts as a scaffold for EWS-FLI1 binding to GGAA repeats, leading to a putative phase transition based upon high concentration of EWS domains. A series of panels (A–D) shows sequential binding of EWS-FLI1 (purple with helical region) to GGAA (red/green) repeats in the DNA. The high concentration of EWS domains that would occur as a result of multiple EWS-FLI1 proteins binding in a DNA microsatellite could lead to a phase transition based upon the intrinsically disordered low-complexity repeats. (E) The increased local concentration of these EWS domain subunits have emergent properties, at a critical concentration depicted here as five proteins, because of a phase transition leading to the sequestration of RNA (cyan). The assemblage and its interaction with RNA could be part of the transcriptional or posttranscriptional machinery. The capture of RNA could tether this dynamic phase separated assemblage to the nascent pre-mRNA or to the posttranscriptional splicing complex.

Mentions: The intrinsically disordered, low-complexity region of EWS, like the other TET proteins, contains repeats of the [G/S]Y[G/S] motif as well as the sequence SYGQQS, a repetitive glutamine-rich motif with prion-like properties (King et al., 2012; Malinovska et al., 2013). The carboxy terminal of EWS contains RNA-binding domains, homologous to those found in other RNA-binding proteins that form well-characterized assemblages (Han et al., 2012). The role of the intrinsically disordered low-complexity domains of EWS in the EWS-FLI1 fusion protein was discussed for many years (Üren et al., 2004; Ng et al., 2007). Recent evidence suggests that polymerization of the low-complexity domains forms an assemblage that can aberrantly recruit other cellular proteins (Kwon et al., 2013). This assemblage is postulated on the basis of the GGAA microsatellite repeats that would drive a high local concentration of EWS-FLI1 through interactions with the DNA-binding domain of FLI1 (Fig. 3). Both the EWS domain and the carboxy-terminal domain of FLI1 have low-complexity amino acid sequences that have the potential to create an assemblage at sites of transcription (Dunker and Uversky, 2010). Together with examples drawn from developmental biology, such as P granules (Feric and Brangwynne, 2013), and cancer biology such as TET proteins (Kwon et al., 2013), pathological assemblages may be dissolved (or allosterically inhibited) by peptides or small molecules that mimic or block the interactions that drive phase transitions.


Assemblages: functional units formed by cellular phase separation.

Toretsky JA, Wright PE - J. Cell Biol. (2014)

DNA acts as a scaffold for EWS-FLI1 binding to GGAA repeats, leading to a putative phase transition based upon high concentration of EWS domains. A series of panels (A–D) shows sequential binding of EWS-FLI1 (purple with helical region) to GGAA (red/green) repeats in the DNA. The high concentration of EWS domains that would occur as a result of multiple EWS-FLI1 proteins binding in a DNA microsatellite could lead to a phase transition based upon the intrinsically disordered low-complexity repeats. (E) The increased local concentration of these EWS domain subunits have emergent properties, at a critical concentration depicted here as five proteins, because of a phase transition leading to the sequestration of RNA (cyan). The assemblage and its interaction with RNA could be part of the transcriptional or posttranscriptional machinery. The capture of RNA could tether this dynamic phase separated assemblage to the nascent pre-mRNA or to the posttranscriptional splicing complex.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4151146&req=5

fig3: DNA acts as a scaffold for EWS-FLI1 binding to GGAA repeats, leading to a putative phase transition based upon high concentration of EWS domains. A series of panels (A–D) shows sequential binding of EWS-FLI1 (purple with helical region) to GGAA (red/green) repeats in the DNA. The high concentration of EWS domains that would occur as a result of multiple EWS-FLI1 proteins binding in a DNA microsatellite could lead to a phase transition based upon the intrinsically disordered low-complexity repeats. (E) The increased local concentration of these EWS domain subunits have emergent properties, at a critical concentration depicted here as five proteins, because of a phase transition leading to the sequestration of RNA (cyan). The assemblage and its interaction with RNA could be part of the transcriptional or posttranscriptional machinery. The capture of RNA could tether this dynamic phase separated assemblage to the nascent pre-mRNA or to the posttranscriptional splicing complex.
Mentions: The intrinsically disordered, low-complexity region of EWS, like the other TET proteins, contains repeats of the [G/S]Y[G/S] motif as well as the sequence SYGQQS, a repetitive glutamine-rich motif with prion-like properties (King et al., 2012; Malinovska et al., 2013). The carboxy terminal of EWS contains RNA-binding domains, homologous to those found in other RNA-binding proteins that form well-characterized assemblages (Han et al., 2012). The role of the intrinsically disordered low-complexity domains of EWS in the EWS-FLI1 fusion protein was discussed for many years (Üren et al., 2004; Ng et al., 2007). Recent evidence suggests that polymerization of the low-complexity domains forms an assemblage that can aberrantly recruit other cellular proteins (Kwon et al., 2013). This assemblage is postulated on the basis of the GGAA microsatellite repeats that would drive a high local concentration of EWS-FLI1 through interactions with the DNA-binding domain of FLI1 (Fig. 3). Both the EWS domain and the carboxy-terminal domain of FLI1 have low-complexity amino acid sequences that have the potential to create an assemblage at sites of transcription (Dunker and Uversky, 2010). Together with examples drawn from developmental biology, such as P granules (Feric and Brangwynne, 2013), and cancer biology such as TET proteins (Kwon et al., 2013), pathological assemblages may be dissolved (or allosterically inhibited) by peptides or small molecules that mimic or block the interactions that drive phase transitions.

Bottom Line: The partitioning of intracellular space beyond membrane-bound organelles can be achieved with collections of proteins that are multivalent or contain low-complexity, intrinsically disordered regions.These proteins can undergo a physical phase change to form functional granules or other entities within the cytoplasm or nucleoplasm that collectively we term "assemblage." Intrinsically disordered proteins (IDPs) play an important role in forming a subset of cellular assemblages by promoting phase separation.Recent work points to an involvement of assemblages in disease states, indicating that intrinsic disorder and phase transitions should be considered in the development of therapeutics.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, Georgetown University, Washington, DC 20057 jat42@georgetown.edu.

Show MeSH
Related in: MedlinePlus