87
Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session I
34-POS
Board 34
Influence of Phosphorylation State on the Conformation of Antibody Epitopes from the
Polyproline Region of the Tau Protein: A Molecular Dynamics Simulation Study
Neha S. Gandhi
1,2
, Albert Lyons
1,2
, Ricardo L. Mancera
1,2
.
1
Curtin University, Perth, WA, Australia,
2
CHIRI BioSciences Research Precinct, Perth, WA,
Australia.
Tau is a highly soluble microtubule-associated protein (MAP) and its hyperphosphorylation is
linked to several tauopathies. The role of Tau phosphorylation and dephosphorylation during
microtubule (MT) stabilization and the formation of neurofibrillary tangles in Alzheimer’s
disease (AD) is poorly understood. The presence of many hyperphosphorylation sites in the
proline-rich region (PRR) of the Tau protein suggests that the PRR domain may be important in
phosphorylation-induced conformational changes.
1
Phosphorylations at both Thr231/Ser235 and
Ser202/Thr205 in the PRR abolishes the ability of the Tau protein to polymerize tubulin into
MT. We have characterised the structural impact of phosphorylation of the Tau protein by
molecular dynamics (MD) simulations of functional fragments of the AT180 epitope. Salt
bridges, hydrogen bonding and secondary structures were monitored and it was found that
phosphorylation of the Thr231 and Ser235 residues stabilizes a short α-helix that runs from
Ser237 until the first MT binding repeat, in agreement with NMR data.
2
Anti-PHF-tau mAb AT8
recognizes an epitope doubly phosphorylated at Ser202 and Thr205 in the PRR.
3
We have also
characterised the conformation of the AT8 epitope using conventional and scaled MD
simulations, with preliminary results suggesting the presence of turn propensity in the region
pThr205-Arg209. The conformational properties of both epitopes are in stark contrast to circular
dichroism data.
4,5
This structural characterisation will help in understanding of how
phosphorylation regulates Tau's physiological and pathological aspects by disturbing local
conformations.
References:
1. Buee et al., Brain Res Brain Res Rev, 2000; 33:95-130.
2. Sibille et al., Proteins, 2012; 80: 454–462.
3. Porzig et al., Biochem Biophys Res Commun, 2007; 358: 644–649.
4. Bielska AA and Zondlo NJ. Biochemistry, 2006;45(17):5527-37.
5. Brister et al., J Am Chem Soc, 2014; 136 : 3803-3816.
