Transthyretin (TTR) is a homotetrameric transporter of thyroid hormones (THs) and contains a central channel key for TH binding and tetramer stability. TTR dissociation can lead to aggregation and amyloid formation causing severe amyloidosis. TTR structure/function evolution is well described [1] although amyloid formation was only explored in humans. TTR has a highly variable N-terminal which became shorter and more polar during evolution is thought to dictate TH-binding specificity[1]. In x-ray crystal structures, the N-terminal is unstructured and thought to be located in the central channel. We hypothesize that the dynamic N-terminal conformation is important for tetramer stability and amyloidogenesis. To test this, we analyzed recombinant TTR from the fish sea bream (sbTTR)[2] and two mutants, Δ1-6 and Δ1-12. Thioflavin-T binding studies showed that sbTTR formed fibrils at lower pH than the human TTR suggesting lower amyloid propensity. Interestingly, Δ1-12 deletions increased sbTTR amyloid propensity while Δ1-6 abolished it. We posit that these effects are due to altered packing of the N-terminal and exposure of segment 13-19, located at the entrance of the central channel and which, according to amyloid prediction algorithms, is highly amyloidogenic. Notably, a naturally occurring N-terminal mutant of hTTR, hTTRG6S, similarly to our mutant sbTTRΔ1-6 was also reported to be non-amyloidogenic[3]. We used circular dichroism, fluorescence spectroscopy and electron microscopy to compare structural, stability and amyloid properties of these forms of human and fish TTR. The latter include TTR from the ancient fish lamprey, which has the longest known N-terminal. Our goal is to determine the role of the N-terminal, which could be a potential target to block aggregation.We are also exploring TTR as a molecular model of amyloid evolution, in an effort to identify adaptive mechanisms to prevent/modulate amyloidogenesis.