TAILIEUCHUNG - Báo cáo khoa học: Metal ions modulate the folding and stability of the tumor suppressor protein S100A2

The EF-hand protein S100A2 is a cell cycle regulator involved in tumori-genesis, acting through regulation of the p53 activation state. Metal ion-free S100A2 is homodimeric and contains two Ca 2+ -binding sites and two Zn 2+ -binding sites per subunit, whereby the Zn 2+ ion binding to one of the sites is coordinated by residues from two homodimers. | ễFEBS Journal Metal ions modulate the folding and stability of the tumor suppressor protein S100A2 Hugo M. Botelho1 Michael Koch2 Gunter Fritz2 and Claudio M. Gomes1 1 Institute de Tecnologia Quimica e Biologica Universidade Nova de Lisboa Portugal 2 Fachbereich Biologie Universitat Konstanz Germany Keywords cancer metals p53 protein stability protein structure and folding Correspondence C. M. Gomes Instituto de Tecnologia Química e Biológica Universidade Nova de Lisboa Av. da Republica EAN 2780-157 Oeiras Portugal Fax 351 214411277 Tel 351 214469332 E-mail gomes@ Received 26 November 2008 revised 15 January 2009 accepted 19 January 2009 doi The EF-hand protein S100A2 is a cell cycle regulator involved in tumori-genesis acting through regulation of the p53 activation state. Metal ion-free S100A2 is homodimeric and contains two Ca2 -binding sites and two Zn2 -binding sites per subunit whereby the Zn2 ion binding to one of the sites is coordinated by residues from two homodimers. The effect of selective binding of these metal ions was investigated using site-specific mutants which lacked one or both zinc sites. CD analysis of secondary structure changes on metallation showed that Zn2 binding was associated with a decrease in the secondary structure content whereas Ca2 had the opposite effect in two of the three S100A2 mutants studied. The energy of unfolding AGU of the apo wild-type S100A2 was determined to be kJ-mol-1 and the apparent midpoint transition temperature Tm p was C. In addition a detailed study of the urea and thermal unfolding of the S100A2 mutants in different metallation states apo Zn2 and Ca2 was performed. Thermal denaturation experiments showed that Zn2 acts as a destabilizer and Ca2 as a stabilizer of the protein conformation. This suggests a synergistic effect between metal binding protein stability and S100A2 biological activity according to which Ca2 activates and stabilizes the protein the

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