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bioRxiv · 10.1101/2024.09.20.614010

Structural Insights into the Role of the Proline Rich Region in Tau Function

Acosta, K.·Brue, C. R.·Kim, H. J.·Holubovska, P.·Mayne, L.·Murakami, K.·Rhoades, E.
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Abstract

Tau is a microtubule-associated protein that plays an important role in modulating axonal microtubules in neurons. Intracellular tau aggregates are found in a broad class of disorders, including Alzheimers disease, termed tauopathies. Tau is an intrinsically disordered protein, and its structural disorder appears to be critical to its microtubule-related functions. Tubulin binding sites are found in taus proline-rich region (PRR), microtubule binding repeats (MTBR: R1-R4), and pseudo-repeat, R'. While many post-translational modifications have been identified on tau, phosphorylation sites, which both regulate tubulin dimer and microtubule interactions and are correlated with disease, cluster with high frequency within the PRR. Here, we use fluorescence correlation spectroscopy and structural mass spectrometry techniques to characterize the impact of phosphomimic mutations in the PRR on tubulin dimer binding and probe the structure of the PRR-tubulin dimer complex. We find that phosphomimics cumulatively diminish tubulin dimer binding and slow microtubule polymerization. Additionally, we map two [~]15 residue regions of the PRR as primary tubulin dimer binding sites and propose a model in which PRR enhances lateral interactions between tubulin dimers, complementing the longitudinal interactions observed for MTBR. Together these measurements provide insight into the previously overlooked relevance of taus PRR in functional interactions with tubulin. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/614010v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@360dd3org.highwire.dtl.DTLVardef@c5d75aorg.highwire.dtl.DTLVardef@bd76eeorg.highwire.dtl.DTLVardef@cb433c_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Acosta, K., Brue, C. R., Kim, H. J., Holubovska, P., Mayne, L., Murakami, K., Rhoades, E.. 2024-09-24. Structural Insights into the Role of the Proline Rich Region in Tau Function. https://doi.org/10.1101/2024.09.20.614010

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