. Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease. Cell. 2012 Mar 30;149(1):232-44. PubMed.

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  1. This intriguing study claims that a localized conformational switch, in the form of the cis/trans conformation of the prolyl bond separating the phosphorylated Threonine 231 (pThr231) and Proline 232 (Pro232) of Tau, carries toxic properties. In order to make this claim, the authors present several polyclonal antibodies that specifically recognize cis or trans forms of this prolyl bond in tau.

    In a tau peptide phosphorylated at the Thr231 site, the authors find the prolyl bond equilibrium yields 91 percent in the trans conformation, and 9 percent in cis. Earlier studies (Daly et al., Biochemistry 2000; Smet et al., Febs Lett. 2005) mentioned even lesser amounts of the cis conformer form in slightly longer peptides. Our NMR results on full-length tau point in the same direction, with less than 5 percent of the cis form for this particular prolyl bond (I. Landrieu and GL, unpublished results). An, at first, amazing finding is that the cis antibody in an Elisa test recognizes the natural (majorly trans) pThr-Pro as strongly as the pThr-dimethyl-proline containing one, although the presence of two methyl groups on the proline ring forces the prolyl bond to adopt almost exclusively the cis conformation. The authors’ argument that “cis and trans isomers in the phosphopeptide can be interchanged relatively easily” implies that the cis-specific antibody would basically displace the equilibrium towards the all-cis form by continuously sequestering the soluble cis-form. The same argument can evidently be applied to full-length phospho-Tau, thereby rendering a quantification of the initial cis- content at least hazardous. Equally intriguing is the overlap of the described cis-specific polyclonal antibody epitope with the epitope of the AT180/TG3 antibodies. AT180 was raised against purified human paired helical fragments (Goedert et al., 1994), and would thus be expected to recognize the cis isoform if that is the dominant form in PHFs, as the present study suggests. However, we showed earlier that AT180 recognizes, with nanomolar affinity, tau phosphorylated by CDK2/CycA3 (Amniai et al., BBRC 2011) at the pThr231-Pro232 epitope, where it is almost exclusively in the trans form. An experiment whereby the cis peptide (with the dimethyl-proline) would be probed with the AT180 antibody may bring clarity to this apparent contradiction (M. Mercken, personal communication).

    The authors use the modified peptides to confirm the specificity of protein phosphatase 2A (PP2A) for the trans conformation of pThr231-Pro232. Whereas we agree on the trans specificity of PP2A, we did unambiguously show by NMR spectroscopy that PP2A containing the B55 regulatory subunit (which is the one the authors used - see Zhou et al., Mol Cell 2000) does not dephosphorylate the pThr231 position (Landrieu et al., Plos One 2011) but rather the pSer205. Phosphorylation of the Thr231 thereby interferes with the catalytic efficiency of the phosphatase. Because dephosphorylation by PP2A was B55 dependent, we assume that the anchoring of the phospho-Tau substrate to the phosphatase via the regulatory B55 unit is regulated by the phospho-status of Thr231. Pin1 has an effect on the PP2A catalyzed dephosphorylation of phospho-Tau, as it seems to counter-act the negative effect of phospho-Thr231, and thereby stimulates the dephosphorylation of the pSer205 despite the presence of a phospho-Thr231. Whereas it is not clear what exact phosphorylation pattern is generated by the cdc2/CycB kinase used by the authors, disruption of the microtubule (MT) assembly capacity of tau (but not binding to MTs) requires at least three phosphates in the pS202/pS205/pT231/pS235 cluster (Amniai et al., Faseb J 2009). If Pin1 stimulates the dephosphorylation of pSer205, and thereby reduces the phospho content, tau, while still containing the phospho-Thr231, might indeed regain its MT assembly capacity after PP2A treatment (Figure 3G).

    In conclusion, the role of Pin1 in changing the phospho-tau conformation remains of considerable interest, but more work is required to evaluate the importance of its isomerase activity on the cis form of the pT231-P232.

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