**Acknowledgements**

it possible to suggest that phosphorylation and dephosphorylation of serine residues are critical not only for self-assembly of prion domains but also for disassembly by aggregation when required, e.g., termination of stress action on the cell. It was assumed that the presence of tyrosine residues facilitates the formation of hydrogel. In this connection, it should be mentioned that in spite of high similarity of these proteins, relative to other members of the family, the cytoplasmic aggregation of FUS is more toxic that correlates with longer glycine

All proteins of the FET/TET family are characterized by the presence of a zinc-finger motif. The exclusion is the EWS protein in chickens, because here the zinc-finger motif has not been determined [78]. As known, a classic zinc-finger motif forms a loop, where two cysteine residues and two histidine residues bind zinc ions. The main function of a classic zinc-finger motif is the binding of DNA, which corresponds to its structure consisting of two to three betasheets in the N-terminal region of the protein and one alpha-helix in its C-terminal region. As for the FET/TET family of proteins, the amino acid sequence of the zinc-finger motif in them differs significantly from the classic consensus motif (Cys-X2–4-Cys-X3-Phe-X5-Leu-X2-His-X3- His) [83]. It should be noticed here that the amino acid sequence of this motif in proteins FUS and EWS is highly similar, which is preserved in all organisms studied by us. Our plots on the prediction of the structure demonstrated quite well the correspondence of this motif and the predicted structure (**Figure 4**: proteins FUS and EWS, second peak from the bottom, blue). On the contrary, in TAF15, this motif differs somewhat not only from FUS and EWS but also in the organisms studied by us; according to our prediction, it forms no structure (**Figure 4**). It is important that in proteins of the FET/TET family the zinc-finger motif occurs only once, contrary to the classic variant when it occurs as tandem repeats. As a rule, if the zinc-finger motif occurs once and its sequence differs considerably from the canonical one, the functions of this motif can differ remarkably from the classic motif. For example, it can both be bound to RNA and have no relation to the binding of nucleic acids [83]. The removal of this motif together with the terminal part of the FUS molecule did not affect the protein ability to aggregate and have toxicity either in yeasts or in the cell culture of the SH-SY5Y neuroblastoma [67]. Additional studies should be conducted to reveal the functions of the zinc-finger motif

**6. Conclusion: Repeats are a general characteristics of prion-like domains**

In this study, we have analyzed RNA-binding proteins with prion-like domains, such as TAF15, FUS, and EWS. Using the FoldAmyloid program [77], we revealed the existence of amyloidogenic regions in the RRM domain in all three proteins of the FET family. This allows us to suggest that when the binding to RNA is violated, the proteins can aggregate spontane‐ ously forming amyloid fibrils. In this case, protein FUS can aggregate both upon the removal of RRM and at point mutations in this domain [65, 66]. Further studies should be conducted to clarify whether aggregation of protein FUS in the presence of RRM does not lead to the

repeats in the amino acid sequence of FUS [33].

112 Update on Amyotrophic Lateral Sclerosis

in proteins of the FET/TET family.

**5.4. Zinc-finger motif in proteins of the FET family**

I thank T.B. Kuvshinkina, E.I. Leonova, I.V. Sokolovsky, and N.V. Dovidchenko for assistance in the chapter preparation. This study was supported by the Russian Science Foundation No. 14-14-00536.
