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The structure of human SFPQ reveals a coiled-coil mediated polymer essential for functional aggregation in gene regulation.

Lee M, Sadowska A, Bekere I, Ho D, Gully BS, Lu Y, Iyer KS, Trewhella J, Fox AH, Bond CS - Nucleic Acids Res. (2015)

Bottom Line: Small-angle X-ray scattering and transmission electron microscopy experiments show that polymerization is reversible in solution and can be templated by DNA.We demonstrate that the ability to polymerize is essential for the cellular functions of SFPQ: disruptive mutation of the coiled-coil interaction motif results in SFPQ mislocalization, reduced formation of nuclear bodies, abrogated molecular interactions and deficient transcriptional regulation.The coiled-coil interaction motif thus provides a molecular explanation for the functional aggregation of SFPQ that directs its role in regulating many aspects of cellular nucleic acid metabolism.

View Article: PubMed Central - PubMed

Affiliation: School of Chemistry and Biochemistry, University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.

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A general model for cooperative nucleic acid-templated functional polymerization of DBHS proteins.
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Figure 8: A general model for cooperative nucleic acid-templated functional polymerization of DBHS proteins.

Mentions: The dynamic and functional aggregation exhibited by SFPQ thus explains its ability to participate in many cellular processes, modulated by local protein and nucleic acid concentrations, thereby providing temporal and spatial regulation and potentially reducing biological noise. A general model for DBHS participation in these processes could involve a seeding event, such as binding to a hotspot in a nucleic acid (e.g. a specific DNA promoter sequence, a DNA double-strand break or a binding site on a long non-coding RNA), followed by condensation of additional DBHS dimers via protein–protein and protein–nucleic acid interactions (Figure 8). Such an assembly, as observed by electron microscopy (Figure 5a), would provide a large local concentration of other peripheral domains of DBHS proteins thus allowing the bulk recruitment of additional factors which could be crucial in mounting a rapid response to DNA damage or a transcriptional event. Similar themes are emerging to explain the involvement of higher order assemblies in signaling complexes (50). Interestingly, the network of coiled-coil interactions observed in the crystals, is redolent of a fibrillar gel. This fibrillar potential is reminiscent of recent discoveries that several other paraspeckle proteins, namely FUS, EWS and TAF15, harbor low complexity domains that form reversible, fibrillar functional aggregates in vivo and in vitro (51,52). These fibrillar mesh networks with liquid like and phase-transition properties mediate the recruitment of the C-terminal domain of RNA polymerase II to promoters, resulting in strong transcriptional activation (52). Analogous to these low-complexity domains, the findings presented in this study offer a framework how a common coiled-coil domain, in combination with nucleic acid binding domains, can form reversible functional aggregates. This framework provides new insight into the multifunctional biological implications of SFPQ in the organization of dynamic sub-cellular structures and gene regulation.


The structure of human SFPQ reveals a coiled-coil mediated polymer essential for functional aggregation in gene regulation.

Lee M, Sadowska A, Bekere I, Ho D, Gully BS, Lu Y, Iyer KS, Trewhella J, Fox AH, Bond CS - Nucleic Acids Res. (2015)

A general model for cooperative nucleic acid-templated functional polymerization of DBHS proteins.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402515&req=5

Figure 8: A general model for cooperative nucleic acid-templated functional polymerization of DBHS proteins.
Mentions: The dynamic and functional aggregation exhibited by SFPQ thus explains its ability to participate in many cellular processes, modulated by local protein and nucleic acid concentrations, thereby providing temporal and spatial regulation and potentially reducing biological noise. A general model for DBHS participation in these processes could involve a seeding event, such as binding to a hotspot in a nucleic acid (e.g. a specific DNA promoter sequence, a DNA double-strand break or a binding site on a long non-coding RNA), followed by condensation of additional DBHS dimers via protein–protein and protein–nucleic acid interactions (Figure 8). Such an assembly, as observed by electron microscopy (Figure 5a), would provide a large local concentration of other peripheral domains of DBHS proteins thus allowing the bulk recruitment of additional factors which could be crucial in mounting a rapid response to DNA damage or a transcriptional event. Similar themes are emerging to explain the involvement of higher order assemblies in signaling complexes (50). Interestingly, the network of coiled-coil interactions observed in the crystals, is redolent of a fibrillar gel. This fibrillar potential is reminiscent of recent discoveries that several other paraspeckle proteins, namely FUS, EWS and TAF15, harbor low complexity domains that form reversible, fibrillar functional aggregates in vivo and in vitro (51,52). These fibrillar mesh networks with liquid like and phase-transition properties mediate the recruitment of the C-terminal domain of RNA polymerase II to promoters, resulting in strong transcriptional activation (52). Analogous to these low-complexity domains, the findings presented in this study offer a framework how a common coiled-coil domain, in combination with nucleic acid binding domains, can form reversible functional aggregates. This framework provides new insight into the multifunctional biological implications of SFPQ in the organization of dynamic sub-cellular structures and gene regulation.

Bottom Line: Small-angle X-ray scattering and transmission electron microscopy experiments show that polymerization is reversible in solution and can be templated by DNA.We demonstrate that the ability to polymerize is essential for the cellular functions of SFPQ: disruptive mutation of the coiled-coil interaction motif results in SFPQ mislocalization, reduced formation of nuclear bodies, abrogated molecular interactions and deficient transcriptional regulation.The coiled-coil interaction motif thus provides a molecular explanation for the functional aggregation of SFPQ that directs its role in regulating many aspects of cellular nucleic acid metabolism.

View Article: PubMed Central - PubMed

Affiliation: School of Chemistry and Biochemistry, University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.

Show MeSH
Related in: MedlinePlus