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Titolo:
Evidence that familial hypercholesterolemia mutations of the LDL receptor cause limited local misfolding in an LDL-A module pair
Autore:
North, CL; Blacklow, SC;
Indirizzi:
Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA Brigham & Womens Hosp Boston MA USA 02115 pt Pathol, Boston, MA 02115 USA Harvard Univ, Sch Med, Boston, MA 02115 USA Harvard Univ Boston MA USA 02115 vard Univ, Sch Med, Boston, MA 02115 USA
Titolo Testata:
BIOCHEMISTRY
fascicolo: 43, volume: 39, anno: 2000,
pagine: 13127 - 13135
SICI:
0006-2960(20001031)39:43<13127:ETFHMO>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
DENSITY-LIPOPROTEIN RECEPTOR; CULTURED HUMAN FIBROBLASTS; GROWTH-FACTOR PRECURSOR; FACTOR-LIKE DOMAINS; EGF-LIKE DOMAIN; CALCIUM-BINDING; CYSTEINE-RICH; MARFAN-SYNDROME; STRUCTURAL INTEGRITY; DIFFERENT PROTEINS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
44
Recensione:
Indirizzi per estratti:
Indirizzo: Blacklow, SC Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA02115 USA Brigham & Womens Hosp 75 Francis St Boston MA USA 02115 5 USA
Citazione:
C.L. North e S.C. Blacklow, "Evidence that familial hypercholesterolemia mutations of the LDL receptor cause limited local misfolding in an LDL-A module pair", BIOCHEM, 39(43), 2000, pp. 13127-13135

Abstract

Mutations at conserved sites within the ligand-binding LDL-A modules of the LDL receptor cause the genetic disease familial hypercholesterolemia (FH), and several of these FH mutations in modules five and six prevent the isolated single modules from folding properly to a nativelike three-dimensional structure. Because LDL-A modules occur as a series of contiguous repeats in the LDLR and related proteins, we investigated the impact of two FH mutations in LDL-A module five (D203G and D206E) and two mutations in module six (E219K and D245E) in the context of the covalently connected module five-six pair. HPLC chromatography of the products formed under conditions that efficiently refold the native module five-six pair demonstrate that, for each mutation, a folding defect persists in the module pair. NMR spectroscopyand calcium affinity measurements of the ensemble of misfolded products demonstrate that the unaltered module of each pair can fold to its native structure regardless of the range of misfolded conformations adopted by its mutated neighbor. These findings lend additional support to a model in which individual LDL-A modules of the LDL receptor act as independent structural elements.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/12/20 alle ore 06:39:32