Document Detail


The preaggregated state of an amyloidogenic protein: hydrostatic pressure converts native transthyretin into the amyloidogenic state.
MedLine Citation:
PMID:  10841549     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Protein misfolding and aggregation cause several diseases, by mechanisms that are poorly understood. The formation of amyloid aggregates is the hallmark of most of these diseases. Here, the properties and formation of amyloidogenic intermediates of transthyretin (TTR) were investigated by the use of hydrostatic pressure and spectroscopic techniques. Native TTR tetramers (T(4)) were denatured by high pressure into a conformation that exposes tryptophan residues to the aqueous environment. This conformation was able to bind the hydrophobic probe bis-(8-anilinonaphthalene-1-sulfonate), indicating persistence of elements of secondary and tertiary structure. Lowering the temperature facilitated the pressure-induced denaturation of TTR, which suggests an important role of entropy in stabilizing the native protein. Gel filtration chromatography showed that after a cycle of compression-decompression at 1 degrees C, the main species present was a tetramer, with a small population of monomers. This tetramer, designated T(4)*, had a non-native conformation: it bound more bis-(8-anilinonaphthalene-1-sulfonate) than native T(4), was less stable under pressure, and on decompression formed aggregates under mild acidic conditions (pH 5-5.6). Our data show that hydrostatic pressure converts native tetramers of TTR into an altered state that shares properties with a previously described amyloidogenic intermediate, and it may be an intermediate that lies on the aggregation pathway. This "preaggregated" state, which we call T(4)*, provides insight into the question of how a correctly folded protein may degenerate into the aggregation pathway in amyloidogenic diseases.
Authors:
A D Ferrão-Gonzales; S O Souto; J L Silva; D Foguel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  97     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2000 Jun 
Date Detail:
Created Date:  2000-07-13     Completed Date:  2000-07-13     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  6445-50     Citation Subset:  IM    
Affiliation:
Programa de Biologia Estrutural, Departamento de Bioquimica Médica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
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MeSH Terms
Descriptor/Qualifier:
Amyloid / metabolism*
Hydrogen-Ion Concentration
Hydrostatic Pressure
Prealbumin / metabolism*
Temperature
Chemical
Reg. No./Substance:
0/Amyloid; 0/Prealbumin
Comments/Corrections

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