Linked Life Data

7577941

Source:http://linkedlifedata.com/resource/pubmed/id/7577941

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
41
pubmed:dateCreated
1995-12-14
pubmed:abstractText
The role that transthyretin (TTR) mutations play in the amyloid disease familial amyloid polyneuropathy (FAP) has been probed by comparing the biophysical properties of several TTR variants as a function of pH. We have previously demonstrated that the partial acid denaturation of TTR is sufficient to effect amyloid fibril formation by self-assembly of a denaturation intermediate which appears to be monomeric. Earlier studies on the most pathogenic FAP variant known, Leu-55-Pro, revealed that this variant is much less stable toward acid denaturation than wild-type TTR, apparently explaining why this variant can form amyloid fibrils under mildly acidic conditions where wild-type TTR remains nonamyloidogenic. The hypothesis that FAP mutations destabilize the TTR tetramer in favor of a monomeric amyloidogenic intermediate under lysosomal (acidic) conditions is further supported by the data described here. We compare the acid stability and amyloidogenicity of the most prevalent FAP variant, Val-30-Met, along with the double mutant, Val-30-Met/Thr-119-Met, which serves to model the effects of these mutations in heterozygous patients where the mutations are in different subunits. In addition, we have characterized the Thr-119-Met TTR variant, which is a common nonpathogenic variant in the Portuguese population, to further investigate the role that this mutation plays in protecting individuals who also carry the Val-30-Met mutation against the classically severe FAP pathology. This biophysical study demonstrates that Val-30-Met TTR is significantly less stable toward acid denaturation and more amyloidogenic than wild-type TTR, which in turn is less stable and more amyloidogenic than Thr-119-Met TTR. Interestingly, the double mutant Val-30-Met/Thr-119-Met is very similar to wild-type TTR in terms of its stability toward acid denaturation and its amyloidogenicity. The data suggest that the Thr-119-Met mutation confers decreased amyloidogenicity by stabilizing tetrameric TTR toward acid denaturation. In addition, fluorescence studies monitoring the acid-mediated denaturation pathways of several TTR variants reveal that the majority exhibit a plateau in the relative fluorescence intensity over the amyloid-forming pH range, i.e., ca. pH 4.3-3.3. This intensity plateau suggests that the amyloidogenic intermediate(s) is (are) being observed over this pH range. The Thr-119-Met variant does not exhibit this plateau presumably because the amyloidogenic intermediate(s) do(es) not build up in concentration in this variant. The intermediate is undoubtedly forming in the Thr-119-Met variant, as it will form amyloid fibrils at high concentrations; however, the intermediate is only present at a low steady-state concentration which makes it difficult to detect.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
17
pubmed:volume
34
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
13527-36
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:7577941-Amino Acid Sequence, pubmed-meshheading:7577941-Amyloidosis, pubmed-meshheading:7577941-Base Sequence, pubmed-meshheading:7577941-DNA Primers, pubmed-meshheading:7577941-Electrophoresis, Polyacrylamide Gel, pubmed-meshheading:7577941-Genes, Lethal, pubmed-meshheading:7577941-Genetic Variation, pubmed-meshheading:7577941-Humans, pubmed-meshheading:7577941-Hydrogen-Ion Concentration, pubmed-meshheading:7577941-Kinetics, pubmed-meshheading:7577941-Leucine, pubmed-meshheading:7577941-Lysosomes, pubmed-meshheading:7577941-Macromolecular Substances, pubmed-meshheading:7577941-Models, Molecular, pubmed-meshheading:7577941-Molecular Sequence Data, pubmed-meshheading:7577941-Mutagenesis, Site-Directed, pubmed-meshheading:7577941-Point Mutation, pubmed-meshheading:7577941-Prealbumin, pubmed-meshheading:7577941-Proline, pubmed-meshheading:7577941-Protein Denaturation, pubmed-meshheading:7577941-Protein Structure, Secondary, pubmed-meshheading:7577941-Recombinant Proteins, pubmed-meshheading:7577941-Structure-Activity Relationship
pubmed:year
1995
pubmed:articleTitle
Comparison of lethal and nonlethal transthyretin variants and their relationship to amyloid disease.
pubmed:affiliation
Department of Chemistry, Texas A&M University, College Station 77843, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't