Biochemical Properties and Biological Functions of FET Proteins

Abstract

Members of the FET protein family, consisting of FUS, EWSR1, and TAF15, bind to RNA and contribute to the control of transcription, RNA processing, and the cytoplasmic fates of messenger RNAs in metazoa. FET proteins can also bind DNA, which may be important in transcription and DNA damage responses. FET proteins are of medical interest because chromosomal rearrangements of their genes promote various sarcomas and because point mutations in FUS or TAF15 can cause neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. Recent results suggest that both the normal and pathological effects of FET proteins are modulated by low-complexity or prion-like domains, which can form higher-order assemblies with novel interaction properties. Herein, we review FET proteins with an emphasis on how the biochemical properties of FET proteins may relate to their biological functions and to pathogenesis.

Keywords: EWSR1; FUS; RNA-binding; TAF15; low-complexity; neurodegeneration.

Figure 1

Conservation of FET proteins throughout multicellular organisms. The diversity of FET proteins expands in multicellular organisms in parallel to the expansion of heterogeneous nuclear ribonucleoprotein particle (hnRNP) proteins. The domain composition of the FET proteins is consistent, although—at least for Arabidopsis thaliana—the order of the domains is somewhat altered. Low-complexity (LC) domains, with their repeated LC motif, are conserved, and the number of motif repeats can vary. RGG domains contain repeats of Arg–Gly–Gly. The asterisk indicates that there are 24 sea urchin hnRNP proteins, although tubeworms are reported to possess only 16 hnRNP proteins. Abbreviations: C4 ZnF, zinc-finger domain anchored by four cysteine residues; RRM, RNA recognition motif.

Figure 2

(a) Summary of the activities and characteristics associated with the domains of FET proteins. The asterisk indicates that the first RGG domain is not very apparent in the protein TAF15 or cabeza and is limited to two RGG motifs within the low-complexity (LC) domain. (b) The relative size of domains (color coded as in panel a) for FUS, EWSR1, TAF15, and cabeza. Abbreviations: ALS, amyotrophic lateral sclerosis; CTD, C-terminal domain; NLS, nuclear localization signal; RNA Pol II, RNA polymerase II; RRM, RNA recognition motif; ZnF, zinc-finger domain.

Figure 3

Model for RNA-nucleated assembly of FUS proteins and recruitment of RNA polymerase II (Pol II). FUS binds RNA highly cooperatively. The FUS–RNA complex forms the seed for fiber growth. FUS fibers are composed of a seed of FUS protein bound to RNA and FUS proteins not bound to RNA. The C-terminal domain (CTD) of RNA Pol II may interact with this fiber either by intercalating into the growing fiber or by binding alongside the fibrous structure.

Figure 4

Two mechanisms by which FET proteins affect transcription. (a) FET proteins, based on the local concentration of RNA transcripts, may form higher-order assemblies near the promoters and transcription start sites of genes. These assemblies recruit more RNA polymerase II (RNA Pol II) through interactions with the C-terminal domain (CTD) and protect the CTD from premature phosphorylation at position Ser2. (b) FUS and EWSR1 interact with several transcription factors to stimulate or repress their activity.