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J. Biol. Chem., Vol. 281, Issue 4, 2333-2337, January 27, 2006

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Human SOD1 before Harboring the Catalytic Metal

SOLUTION STRUCTURE OF COPPER-DEPLETED, DISULFIDE-REDUCED FORM^*

Lucia Banci, Ivano Bertini1, Francesca Cantini, Nicola D'Amelio¶, and Elena Gaggelli¶

From the Magnetic Resonance Center, University of Florence, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy, Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy, and ^¶Department of Chemistry, University of Siena, Via Aldo Moro, 53100 Siena, Italy

SOD1 has to undergo several post-translational modifications before reaching its mature form. The protein requires insertion of zinc and copper atoms, followed by the formation of a conserved S-S bond between Cys-57 and Cys-146 (human numbering), which makes the protein fully active. In this report an NMR structural investigation of the reduced SH-SH form of thermostable E,Zn-as-SOD1 (E is empty; as is C6A, C111S) is reported, characterizing the protein just before the last step leading to the mature form. The structure is compared with that of the oxidized S-S form as well as with that of the yeast SOD1 complexed with its copper chaperone, CCS. Local conformational rearrangements upon disulfide bridge reduction are localized in the region near Cys-57 that is completely exposed to the solvent in the present structure, at variance with the oxidized forms. There is a local disorder around Cys-57 that may serve for protein-protein recognition and may possibly be involved in intermolecular S-S bonds in familial amyotrophic lateral sclerosis-related SOD1 mutants. The structure allows us to further discuss the copper loading mechanism in SOD1.

Received for publication, June 15, 2005 , and in revised form, October 3, 2005.

The atomic coordinates and structure factors (code 2AF2) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by MIUR-COFIN 2003, UPMAN LSHG-CT-2004-512052, and the European Commission (QLG2-CT-2002-00988 and SPINE QLG2-CT-2002-00988). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5 and supplemental Tables S1 and S2.

¹ To whom correspondence should be addressed. Tel.: 39-055-4574272; Fax: 39-055-4574271; E-mail: ivanobertini{at}cerm.unifi.it.

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