The importance of a gatekeeper residue on the aggregation of transthyretin: implications to transthyretin-related amyloidoses [Protein Structure and Folding]

August 1st, 2014 by Sant'Anna, R., Braga, C., Vareȷao, N., Pimenta, K. M., Grana–Montes, R., Alves, A., Cortines, J., Cordeiro, Y., Ventura, S., Foguel, D.

Protein aggregation into β-sheet enriched amyloid fibrils is associated with an increasing number of human disorders. The adoption of such amyloid conformations seems to constitute a generic property of polypeptide chains. Therefore, during evolution, proteins have adopted negative design strategies to diminish their intrinsic propensity to aggregate, including enrichment of gatekeeper charged residues at the flanks of hydrophobic aggregation-prone segments. Wild type TTR is responsible for senile systemic amyloidosis and more than 100 mutations in the TTR gene are involved in familial amyloid polyneuropathy. The 26-57 TTR segment bears many of these aggressive amyloidogenic mutations as well as the binding site for heparin. We demonstrate here that K35 acts as a gatekeeper residue in TTR, strongly decreasing its amyloidogenic potential. This protective effect is sequence specific, since K48 does not affect TTR aggregation. K35 is part of the TTR basic heparin-binding motif. This glycosaminoglycan blocks the protective effect of K35, likely by neutralization of its side chain positive charge. A K35L mutation emulates this effect and results in the rapid self-assembly of the 26-57 TTR region into amyloid fibrils. This mutation does not affect the tetrameric protein stability, but strongly increases its aggregation propensity. Overall, we illustrate how TTR is yet another amyloidogenic protein exploiting negative design to prevent its massive aggregation and we show how blockage of conserved protective features by endogenous factors or mutations might result in increased disease susceptibility.
  • Posted in Journal of Biological Chemistry, Publications
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