. A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing. EMBO J. 2018 Mar 1;37(5) Epub 2018 Feb 9 PubMed.


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  1. In my opinion, this paper represents an important advance. Last July, together with Emanuele Buratti's lab in Trieste, we published on the N-terminal domain of TDP-43 and a structural model of its dimer at pH 4.0 (Mompeán et al., 2017). At neutral pH this domain has low solubility and tends to self-associate at neutral pH, which makes it very hard to characterize structurally. Our model, at pH 4, pointed to a dimer with a head-to-head configuration.

    A June 2017 paper by Polymenidou and Allain's laboratories reported the X-ray structure of the N-terminal domain of TDP-43 at neutral pH, which showed oligomeric structure with head-to-tail contacts between the N-terminal domains (Afroz et al., 2017). Like ourselves, Polymenidou's paper proposed that the N-terminal domain's oligomerization would act to orient the C-terminal regions away from each other, and would help reduce their tendency to pathologically aggregate in ALS.

    Building on this background, Fawzi and Alaya's paper makes new important advances. They cleverly introduced mutations to limit the N-terminal domain (NTD) oligomerization to the dimer stage, which allowed them to characterize its structure in solution by NMR. Importantly, in this way they could confirm the head-to-tail configuration seen by Polymenidou et al. This was important because protein quaternary contacts can be influenced by crystal packing. Secondly, they found that serine 48 can be phosphorylated and that this post-translational modification would disrupt N-terminal domain oligomerization. In contrast to the idea proposed by us and seconded by Polymendiou, that the NTD disfavors the C-terminal region harmful aggregation, Fawzi et al. proposed that NTD oligomerization tends to favor the C-terminal aggregation, unless Ser 48 is phosphorylated. This proposal is attractive because it would explain many previous studies showing that the N-terminal domain is needed both for physiological association (such as healthy association into the stress granule) and harmful aggregation. I would expect that future studies will focus on confirming the extent to which Ser 48 is phosphorylated in cells and further characterize its physiological and pathological actions.


    . Point mutations in the N-terminal domain of transactive response DNA-binding protein 43 kDa (TDP-43) compromise its stability, dimerization, and functions. J Biol Chem. 2017 Jul 14;292(28):11992-12006. Epub 2017 May 31 PubMed.

    . Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation. Nat Commun. 2017 Jun 29;8(1):45. PubMed.

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