title: Jagged-1 juxtamembrane region: biochemical characterization and cleavage by ADAM17 (TACE) catalytic domain.
abstract: Ectodomain shedding of membrane receptors and ligands carried out by ADAMs (A disintegrin and metalloprotease) plays a major role in several signaling pathways, including Notch. The grounds of substrate recognition, however, are poorly understood. We demonstrate that a recombinant protein corresponding to the juxtamembrane region of Jagged-1, one of the Notch ligands, behaves as a structured module and is cleaved by ADAM17 catalytic domain at E1054. A short synthetic peptide is cleaved at the same site but at a much higher rate, implying that the structure of the cleavage site in the native protein is a key determinant for substrate recognition. We also show that an Alagille syndrome-associated mutation near E1054 increases the cleavage rate, which suggests that this mutation may lead to an unbalance in Notch signaling due to a higher level of Jagged-1 shedding.
authors: Protein Structure and Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), AREA Science Park, Padriciano 99, I-34149 Trieste, Italy.
authors: Maristella
authors: M
authors: Coglievina
authors: Corrado
authors: C
authors: Guarnaccia
authors: Ventsislav
authors: V
authors: Zlatev
authors: Sándor
authors: S
authors: Pongor
authors: Alessandro
authors: A
authors: Pintar
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry*; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D020134:Catalytic Domain; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D008969:Molecular Sequence Data; D059748:Proteolysis; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human