Electronic Journal of Biotechnology
ISSN: 0717-3458 |
© 2000 by Universidad
Católica de Valparaíso -- Chile |
Protein Stability
in Health and Disease: Human Transthyretin, a Case Study
Rui M.M. Brito*
Centro de Neurociências de
Coimbra, Universidade de coimbra, 3000 Coimbra
Departamento de Química, FCT, Universidade de Coimbra, 3049 Coimbra
Portugal
Alexandre
Quintas
Centro de Neurociências de
Coimbra, Universidade de coimbra, 3000 Coimbra
Inst. Superior Ciências de Saúde Sul, 2825 Monte da Caparica
Portugal
Daniela C.
Vaz
Centro de Neurociências de
Coimbra, Universidade de coimbra, 3000 Coimbra
Portugal
M.J.M. Saraiva
Inst. Ciências Biomédicas
Abel Salazar and Inst. Molecular and Cellular Biology
Universidade do Porto, 4050 Porto
Portugal
*Corresponding Author
This work was supported
in part by grants PRAXIS/SAU/1287/95 and BIOMED 963689
Amyloid fibril formation
and deposition are the basis for a wide range of diseases, including
spongiform encephalopathies, Alzheimer's and Familial Amyloidotic Polyneuropathies
(FAP). In certain forms of FAP, the amyloid fibrils are mostly constituted
by variants of transthyretin (TTR), a homo-tetrameric protein with a
total molecular weight of 55 kDa and 127 aminoacid residues per subunit,
found in the cerebrospinal fluid and in the plasma. Until recently a
lot of emphasis has been placed on the role of a low pH environment,
for example found in the lysosomes, being required to dissociate the
native tetrameric TTR and induce the formation of a monomeric amyloidogenic
intermediate (Kelly (1998) Curr Opin Struct Biol 8, 101). We have reported
on the isolation of TTR monomeric species at pH 7.0, near physiological
ionic strengths and commonly encountered physiological protein concentrations
(Quintas et al.I, (1997) FEBS Lett 418, 297). Based on several biophysical
studies, we have also shown that this monomeric species is non-native
and we proposed a model for amyloidogenesis, at commonly observed physiological
conditions (Quintas et al., (1999) J. Biol. Chem in press). Here, we
additionally report on the correlation between protein stability to
chemical unfolding and the amyloidogenic potential of several TTR variants.
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