Amyloid Formation by Human Carboxypeptidase D Transthyretin-like Domain Under Physiological Conditions [Molecular Biophysics]

October 7th, 2014 by Garcia–Pardo, J., Grana–Montes, R., Fernandez–Mendez, M., Ruyra, A., Roher, N., Aviles, F. X., Lorenzo, J., Ventura, S.

Protein aggregation is linked to a growing list of diseases, but is also an intrinsic property of polypeptides, since the formation of functional globular proteins comes at the expense of an inherent aggregation propensity. Certain proteins can access aggregation-prone states from native-like conformations without the need to cross the energy barrier for unfolding. This is the case of transthyretin (TTR), a homotetrameric protein whose dissociation into its monomers initiates the aggregation cascade. Domains with structural homology to TTR exist in a number of proteins, including M14B subfamily carboxypeptidases (CPs). We show here that the monomeric transthyretin-like domain of human CPD (h-TTL) aggregates under close to physiological conditions into amyloid structures, the population of folded but aggregation-prone states being controlled by the conformational stability of the domain. We thus confirm that the TTR fold keeps a generic residual aggregation propensity upon folding, resulting from the presence of preformed amyloidogenic β-strands in the native state. These structural elements should serve for functional/structural purposes, since they have not been purged out by evolution, but at the same time they put proteins like CPD at risk of aggregation in biological environments and thus can potentially lead to deposition diseases.