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Perturbation in Long-Range Contacts Modulates the Kinetics of Amyloid Formation in α‑Synuclein Familial Mutants
journal contribution
posted on 2017-07-31, 00:00 authored by Priyatosh Ranjan, Ashutosh KumarThe characteristic
cross-β-sheet-rich amyloid fibril formation
by intrinsically disordered α-synuclein proteins is one of the
pathological hallmarks of Parkinson’s disease. Although unstructured
in solution, the presence of autoinhibitory long-range contacts in
monomeric form prevents protein aggregation. Out of the various factors
that affect the rate of amyloid formation, familial mutations play
an important role in α-synuclein aggregation. Even though these
mutations are believed to form an aggregation-prone intermediate by
perturbing these contacts, the correlation between perturbation and
rate of fibril formation is not very straightforward. A combination
of solution and solid-state NMR in conjunction with other biophysical
methods has been used to identify the underlying mechanism behind
the anomaly in the rate of aggregation for the novel mutants H50Q
(fast aggregating) and G51D (slow aggregating). Perturbation of long-range
contacts at the mutation sites and C-termini in all of the six familial
mutants of α-synuclein during the diseased condition (acidic
pH) was observed. These contacts get rearranged at physiological pH
resulting in the shielding of mutation sites. Additional contacts
at the mutation site in a slow aggregating mutant could be the reason
for slower aggregation. Indeed, these contacts provide more rigidity
to the monomeric G51D. Nonetheless, these mutations did not alter
the overall secondary structure. The differential pattern of the long-range
contacts at the monomeric level resulted in the perturbation of the
fibrillar-core region, which was evident in the solid-state NMR spectra.
Our results provide valuable insights in understanding the effect
of long-range contacts on the aggregation of α-synuclein and
its mutants.