 |
PDBsum entry 4mrb
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transport protein
|
PDB id
|
|
|
|
4mrb
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Proteolytic cleavage of ser52pro variant transthyretin triggers its amyloid fibrillogenesis.
|
|
|
Authors
|
|
P.P.Mangione,
R.Porcari,
J.D.Gillmore,
P.Pucci,
M.Monti,
M.Porcari,
S.Giorgetti,
L.Marchese,
S.Raimondi,
L.C.Serpell,
W.Chen,
A.Relini,
J.Marcoux,
I.R.Clatworthy,
G.W.Taylor,
G.A.Tennent,
C.V.Robinson,
P.N.Hawkins,
M.Stoppini,
S.P.Wood,
M.B.Pepys,
V.Bellotti.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2014,
111,
1539-1544.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
The Ser52Pro variant of transthyretin (TTR) produces aggressive, highly
penetrant, autosomal-dominant systemic amyloidosis in persons heterozygous for
the causative mutation. Together with a minor quantity of full-length wild-type
and variant TTR, the main component of the ex vivo fibrils was the residue
49-127 fragment of the TTR variant, the portion of the TTR sequence that
previously has been reported to be the principal constituent of type A, cardiac
amyloid fibrils formed from wild-type TTR and other TTR variants [Bergstrom J,
et al. (2005) J Pathol 206(2):224-232]. This specific truncation of Ser52Pro TTR
was generated readily in vitro by limited proteolysis. In physiological
conditions and under agitation the residue 49-127 proteolytic fragment rapidly
and completely self-aggregates into typical amyloid fibrils. The remarkable
susceptibility to such cleavage is likely caused by localized destabilization of
the β-turn linking strands C and D caused by loss of the wild-type
hydrogen-bonding network between the side chains of residues Ser52, Glu54,
Ser50, and a water molecule, as revealed by the high-resolution crystallographic
structure of Ser52Pro TTR. We thus provide a structural basis for the recently
hypothesized, crucial pathogenic role of proteolytic cleavage in TTR amyloid
fibrillogenesis. Binding of the natural ligands thyroxine or retinol-binding
protein (RBP) by Ser52Pro variant TTR stabilizes the native tetrameric assembly,
but neither protected the variant from proteolysis. However, binding of RBP, but
not thyroxine, inhibited subsequent fibrillogenesis.
|
|
|
|
|
|
|
