TAILIEUCHUNG - Báo cáo khoa học: The tetralogy of Fallot-associated G274D mutation impairs folding of the second epidermal growth factor repeat in Jagged-1

Notch signaling controls spatial patterning and cell-fate decisions in all metazoans. Mutations inJAG1, one of the five Notch ligands in man, have been associated with Alagille syndrome and with a familial form of tetral-ogy of Fallot. A specific G274D mutation in the second epidermal growth factor repeat of the Jagged-1 was found to correlate with tetralogy of Fallot symptoms but not with usual Alagille syndrome phenotypes. | ỊFEBS Journal The tetralogy of Fallot-associated G274D mutation impairs folding of the second epidermal growth factor repeat in Jagged-1 Corrado Guarnaccia Somdutta Dhir Alessandro Pintar and Sandor Pongor Protein Structure and Bioinformatics Group InternationalCentre for Genetic Engineering and Biotechnology ICGEB Trieste Italy Keywords Alagille syndrome disease mutation limited proteolysis Notch signaling oxidative folding Correspondence A. Pintar or S. Pongor AREA Science Park Padriciano 99 I-34149 Trieste Italy Fax 39 040 226555 Tel 39 040 3757354 E-mail pintar@ pongor@ Received 30 June 2009 revised 25 August 2009 accepted 27 August 2009 doi Notch signaling controls spatial patterning and cell-fate decisions in all metazoans. Mutations in JAG1 one of the five Notch ligands in man have been associated with Alagille syndrome and with a familial form of tetralogy of Fallot. A specific G274D mutation in the second epidermal growth factor repeat of the Jagged-1 was found to correlate with tetralogy of Fallot symptoms but not with usual Alagille syndrome phenotypes. To investigate the effects of this mutation we studied the in vitro oxidative folding of the wild-type and mutant peptides encompassing the second epidermal growth factor. We found that the G274D mutation strongly impairs the correct folding of the epidermal growth factor module and folding cannot be rescued by compensative mutations. The 274 position displays very low tolerance to substitution because neither the G274S nor the G274A mutants could be refolded in vitro. A sequence comparison of epidermal growth factor repeats found in human proteins revealed that the pattern displayed by the second epidermal growth factor is exclusively found in Notch ligands and that G274 is absolutely conserved within this group. We carried out a systematic and comprehensive analysis of mutations found in epidermal growth factor repeats and show that specific residue .

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