It takes tau to tango: investigating the fuzzy interaction between the tau-R2 repeat and tubulin C-terminal tails
Résumé
Fuzzy complexes are a relatively new type of protein interaction involving one or more intrinsically disordered elements which proved more and more biologically important in the past two decades [2]. Intrinsically disordered protein Tau is known to stabilize microtubules (MT), but little is known regarding its interaction with the intrinsically disordered C-terminal tails (CTTs) of tubulins [3].
We used all-atom molecular dynamics simulations to decipher the behavior of the R2 repeat
domain of the Tau protein in complex with 3 tubulin monomers β-α-β. We built the C-terminal
tails corresponding to isotypes βI-αI-βI and βIII-αI-βIII by homology. Our analysis confirmed the
existence of a highly stable interface area involving Ser289, a serine notably phosphorylated in
Alzheimer’s disease [4], and revealed a modification of the dynamics of CTTs in presence of R2.
The latter result gives more weight to Lessard and Berger’s idea that interactions between kinesins and MT could be indirectly mediated by the presence of Tau [5]. We also propose a “wrapping mechanism” of the CTTs around R2 which might provide more insight regarding the stabilizing impact of CTTs in Tau/MT complexes observed by Hinrichs et al [3].
References
1 Marien J, Prévost C, and Sacquin-Mora S (2023) It takes Tau to tango : Investigating the fuzzy interaction between the Tau-R2 repeat domain and the C-terminal tails of tubulins, bioRxiv 2023.02.09.527845; doi: https://doi.org/10.1101/2023.02.09.527845
2 Sacquin-Mora S, Prévost C. When Order Meets Disorder: Modeling and Function of the Protein Interface in Fuzzy Complexes.
Biomolecules. 2021 Oct 16;11(10):1529. doi: 10.3390/biom11101529. PMID: 34680162; PMCID: PMC8533853.
3 Hinrichs, M. H., Jalal, A., Brenner, B., Mandelkow, E., Kumar, S., and Scholz, T. (2012) Tau protein diffuses along the microtubule lattice, The Journal of biological chemistry 287, 38559-38568, doi: 10.1074/jbc.M112.369785
4 Drummond E, Pires G, MacMurray C, Askenazi M, Nayak S, Bourdon M, Safar J, Ueberheide B, and Wisniewski T. (2020)
Phosphorylated tau interactome in the human Alzheimer's disease brain. Brain. 2020 Sep 1;143(9):2803-2817. doi: 10.1093/brain/awaa223. PMID: 32812023; PMCID: PMC7526722.
5 Lessard, D., and Berger, C. (2021) The Microtubule Associated Protein Tau Regulates KIF1A Pausing Behavior and Motility,
bioRxiv, 2021.2008.2011.455914 ,doi: https://doi.org/10.1101/2021.08.11.455914