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bioRxiv · 10.1101/2020.05.12.091587

Preferred Conformations in the Intrinsically Disordered Region of Human CPEB3 Explain its Role in Memory Consolidation

Ramirez de Mingo, D.·Pantoja-Uceda, D.·Hervas, R.·Carrion-Vazquez, M.·Laurents, D. V.
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Abstract

While implicated in neurodegenerative diseases, amyloids are also essential to some physiological processes, including memory consolidation by neuronal-specific isoforms of the Cytoplasmic Polyadenylation Element Binding (CPEB) protein family. CPEB mediates memory persistence by the formation of self-sustaining amyloid assemblies through its intrinsically disordered region (IDR). Here, we characterize the atomic level conformation and ps-ns dynamics of the 426-residue IDR of human CPEB3 (hCPEB3), which has been associated with episodic memory in humans, by NMR spectroscopy. We found that the first 29 residues: M1QDDLLMDKSKTQPQPQQQQRQQQQPQP29, adopt a helical+disordered motif. Residues 86-93: P83QQPPPP93, and 166-175: P166PPPAPAPQP175 form polyproline II (PPII) helices. While the (VG)5 repeat motif is completely disordered, residues 200-250 adopt three partially populated -helices. Residues 345-355, which comprise the nuclear localization signal (NLS), form a modestly populated -helix and border a phosphoTyr which may mediate STAT5B binding. These findings allow us to suggest a model for nascent hCPEB3 structural transitions at single residue resolution, advancing that amyloid breaker residues, like proline, are a key difference between functional versus pathological amyloids. Besides revealing some aspects of the molecular basis of memory, these findings could aid the future development of treatments for post-traumatic stress disorder. Areas: Biophysics, Structural Biology, Biochemistry & Neurosciences.

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Ramirez de Mingo, D., Pantoja-Uceda, D., Hervas, R., Carrion-Vazquez, M., Laurents, D. V.. 2020-05-14. Preferred Conformations in the Intrinsically Disordered Region of Human CPEB3 Explain its Role in Memory Consolidation. https://doi.org/10.1101/2020.05.12.091587

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