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Titolo:
A ROLE FOR DESTABILIZING AMINO-ACID REPLACEMENTS IN LIGHT-CHAIN AMYLOIDOSIS
Autore:
HURLE MR; HELMS LR; LI L; CHAN WN; WETZEL R;
Indirizzi:
SMITHKLINE BEECHAM PHARMACEUT,DEPT MACROMOLEC SCI,709 SWEDELAND RD KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT MACROMOLEC SCI KING OF PRUSSIA PA 19406
Titolo Testata:
Proceedings of the National Academy of Sciences of the United Statesof America
fascicolo: 12, volume: 91, anno: 1994,
pagine: 5446 - 5450
SICI:
0027-8424(1994)91:12<5446:ARFDAR>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
MONOCLONAL IMMUNOGLOBULIN DEPOSITION; BENCE-JONES PROTEINS; AL; DISEASE; TRANSTHYRETIN; STABILITY; FRAGMENTS; PRECURSOR; MUTATION; SEQUENCE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
44
Recensione:
Indirizzi per estratti:
Citazione:
M.R. Hurle et al., "A ROLE FOR DESTABILIZING AMINO-ACID REPLACEMENTS IN LIGHT-CHAIN AMYLOIDOSIS", Proceedings of the National Academy of Sciences of the United Statesof America, 91(12), 1994, pp. 5446-5450

Abstract

Light-chain (L-chain) amyloidosis is characterized by deposition of fibrillar aggregates composed of the N-terminal L-chain variable region(V-L) domain of an immunoglobulin, generally in individuals overproducing a monoclonal L chain. In addition to proteolytic fragmentation and high protein concentration, particular amino acid substitutions may also contribute to the tendency of an L chain to aggregate in L-chain amyloidosis, although evidence in support of this has been limited anddifficult to interpret. In this paper we identify particular amino acid replacements at specific positions in the V-L domain that are occupied at frequencies significantly higher in those L chains associated with amyloidosis. Analysis of the structural model for the V-L domain of the Bence-Jones protein REI suggests that these positions play important roles in maintaining domain structure and stability. Using an Escherichia coil expression system, we prepared single-point mutants of REI V-L incorporating amyloid-associated amino acid replacements that are both rare and located at structurally important positions. These mutants support ordered aggregate formation in an in vitro L-chain fibril formation model in which wild-type REI V-L remains soluble. Moreover, the ability of these sequences to aggregate in vitro correlates wellwith the extent to which domain stability is decreased in denaturant-induced unfolding. The results are consistent with a mechanism for thedisease process in which the V-L domain, either before or after proteolytic cleavage from the L-chain constant region domain, unfolds by virtue of one or more destabilizing amino acid replacements to generate an aggregation-prone nonnative state.

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Documento generato il 21/09/20 alle ore 18:04:46