Abstract
We used time-resolved FRET, circular dichroism, and all-atom simulation to investigate the structural impact of phosphorylation and dielectric constant on synaptotagmin 1's intrinsically disordered region (IDR). We found that the full-length IDR sequence, a ∼60 residue strong polyampholyte that when studied in the form of a peptide, undergoes structural collapse consistent with its κ-predicted behavior. Furthermore, we found that the exocytosis-modulating phosphorylation of Thr112, a residue located in the IDR's more sequence diverse central core region, disrupts a local disorder-to-order transition that occurs when solution dielectric constant is lowered and helical structure is stabilized by addition of trifluoroethanol. Implicit solvent simulations testing the impact of dielectric constant alone converge on a similar result, showing that helical structure is formed with higher probability at a reduced dielectric, where several lysine-aspartic acid salt bridges stabilize transient secondary structure. Phosphorylation, however, results in formation of salt bridges unsuitable for helix formation. These results suggest a model where compaction of the IDR sequence and phosphorylation may regulate structural transitions that in turn modulate neuronal exocytosis.
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