The
transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or
cardiomyopathy. ATTR are caused by aggregation of
transthyretin (TTR), a natively tetrameric
protein involved in the transport of
thyroxine and the
vitamin A-
retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form
amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted
therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR
amyloid fibril formation. One such compound,
tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of
Transthyretin Type
Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of
disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by
tafamidis.
Tafamidis binds selectively and with negative cooperativity (K(d)s ~2 nM and ~200 nM) to the two normally unoccupied
thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by
tafamidis binding. The crystal structure of
tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.