Comparative calorimetric study of non-amyloidogenic and amyloidogenic variants of the homotetrameric protein transthyretin

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant heredita ry type of amyloidosis involving amino acid substitutions in transthyretin (TTR). V30M-TTR is the most frequent variant, and L55P-TTR is the variant a ssociated with the most aggressive form of FAP. The thermal stability of th e wild-type, V30M-TTR, L55P-TTR and a non-amyloidogenic variant, T119M-TTR, was studied by high-sensitivity differential scanning calorimetry (DSC). T he thermal unfolding of TTR is a spontaneous reversible process involving a highly co-operative transition between folded tetramers and unfolded monom ers. All variants of transthyretin are very stable to the thermal unfolding that occurs at very high temperatures, most probably because of their olig omeric structure. The data presented in this work indicated that for the ho motetrameric form of the wild-type TTR and its variants, the order of stabi lity is as follows: wild-type TTR greater than or similar to T119M-TTR > L5 5P-TTR > V30M-TTR, which does not correlate with their known amyloidogenic potential. (C) 2000 Elsevier Science B.V. All rights reserved.