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Titolo:
Mutations in calcium-binding epidermal growth factor modules render fibrillin-1 susceptible to proteolysis - A potential disease-causing mechanism inMarfan syndrome
Autore:
Reinhardt, DP; Ono, RN; Notbohm, H; Muller, PK; Bachinger, HP; Sakai, LY;
Indirizzi:
Med Univ Lubeck, Dept Med Mol Biol, D-23538 Lubeck, Germany Med Univ Lubeck Lubeck Germany D-23538 Mol Biol, D-23538 Lubeck, Germany Shriners Hosp Crippled Children, Dept Res, Portland, OR 97201 USA ShrinersHosp Crippled Children Portland OR USA 97201 tland, OR 97201 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 16, volume: 275, anno: 2000,
pagine: 12339 - 12345
SICI:
0021-9258(20000421)275:16<12339:MICEGF>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
FACTOR-LIKE DOMAINS; MATRIX METALLOPROTEINASES; POINT MUTATIONS; FBN1 MUTATIONS; GENE; MICROFIBRILS; EXPRESSION; DATABASE; EDITION; PROTEIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Reinhardt, DP Med Univ Lubeck, Dept Med Mol Biol, Ratzeburger Allee 160, D-23538 Lubeck,Germany Med Univ Lubeck Ratzeburger Allee 160 Lubeck GermanyD-23538
Citazione:
D.P. Reinhardt et al., "Mutations in calcium-binding epidermal growth factor modules render fibrillin-1 susceptible to proteolysis - A potential disease-causing mechanism inMarfan syndrome", J BIOL CHEM, 275(16), 2000, pp. 12339-12345

Abstract

Most extracellular proteins consist of various modules with distinct functions. Mutations in one common type, the calcium-binding epidermal growth factor-like module (cbEGF), can lead to a variety of genetic disorders. Here,we describe as a model system structural and functional consequences of two typical mutations in cbEGF modules of fibrillin-1 (N548I, E1073K), resulting in the Marfan syndrome. Large (80-120 kDa) wild-type and mutated polypeptides were recombinantly expressed in mammalian cells. Both mutations did not alter synthesis and secretion of the polypeptides into the culture medium. Electron microscopy after rotary shadowing and comparison of circular dichroism spectra exhibited minor structural differences between the wild-type and mutated forms. The mutated polypeptides were significantly more susceptible to proteolytic degradation by a variety of proteases as compared with their wild-type counterparts. Most of the sensitive cleavage sites were mapped close to the mutations, indicating local structural changes within the mutated cbEGF modules. Other cleavage sites, however, were observed at distances beyond the domain containing the mutation, suggesting longer rangestructural effects within tandemly repeated cbEGF modules. We suggest thatproteolytic degradation of mutated fibrillin-1 may play an important role in the pathogenesis of Marfan syndrome and related disorders.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/11/20 alle ore 07:08:14