FAP mutations destabilize transthyretin facilitating conformational changes required for amyloid formation.
Functional transthyretin (TTR) can be transformed into amyloid by partial acid denaturation yielding a monomeric amyloidogenic intermediate which self-associates. The amyloidogenic intermediate has substantial beta-sheet structure with non-native but defined tertiary structure. pH-dependent proteolysis sensitivity studies have identified portions of TTR which become disordered and solvent-exposed in the amyloidogenic intermediate. These include the C-strand-loop D-strand portion of TTR which moves away from the core of the beta-sandwich fold. Mutations that are associated with early onset-amyloid disease (familial amyloidotic polyneuropathy; FAP) function by destabilizing tetrameric TTR in favour of the monomeric amyloidogenic intermediate which has a rearranged C-strand-loop D-strand region. In most cases the FAP mutations do not significantly alter the native folded structure, but instead act on the denaturation pathway by a mechanism that is not completely understood. Interestingly, mutations have also been characterized which strongly stabilize tetrameric TTR and make amyloid formation very difficult at pHs accessible in vivo.
Colon
W
W
Texas A&M University, College Station 77843-3255, USA.
Lai
Z
Z
McCutchen
S L
SL
Miroy
G J
GJ
Strang
C
C
Kelly
J W
JW
D000682:Amyloid / Q000096:biosynthesis*; D000686:Amyloidosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding
D000682:Amyloid; D011228:Prealbumin