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J Biol Chem ; 284(40): 27567-76, 2009 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-19657145

RESUMEN

Mutations in the TNF family ligand EDA1 cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition characterized by defective development of skin appendages. The EDA1 protein displays a proteolytic processing site responsible for its conversion to a soluble form, a collagen domain, and a trimeric TNF homology domain (THD) that binds the receptor EDAR. In-frame deletions in the collagen domain reduced the thermal stability of EDA1. Removal of the collagen domain decreased its activity about 100-fold, as measured with natural and engineered EDA1-responsive cell lines. The collagen domain could be functionally replaced by multimerization domains or by cross-linking antibodies, suggesting that it functions as an oligomerization unit. Surprisingly, mature soluble EDA1 containing the collagen domain was poorly active when administered in newborn, EDA-deficient (Tabby) mice. This was due to a short stretch of basic amino acids located at the N terminus of the collagen domain that confers EDA1 with proteoglycan binding ability. In contrast to wild-type EDA1, EDA1 with mutations in this basic sequence was a potent inducer of tail hair development in vivo. Thus, the collagen domain activates EDA1 by multimerization, whereas the proteoglycan-binding domain may restrict the distribution of endogeneous EDA1 in vivo.


Asunto(s)
Colágeno/metabolismo , Ectodisplasinas/química , Ectodisplasinas/metabolismo , Proteoglicanos de Heparán Sulfato/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos/farmacología , Muerte Celular , Línea Celular , Reactivos de Enlaces Cruzados/farmacología , Ectodisplasinas/deficiencia , Desarrollo Embrionario , Regulación de la Expresión Génica , Ingeniería Genética , Cabello/crecimiento & desarrollo , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Ratones , FN-kappa B/metabolismo , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Receptores de la Ectodisplasina/metabolismo , Cola (estructura animal)
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