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J. Biol. Chem., Vol. 278, Issue 24, 21837-21844, June 13, 2003

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Solution Structural Studies on Human Erythrocyte -Spectrin Tetramerization Site^*

Sunghyouk Park , Michael S. Caffrey , Michael E. Johnson  ¶ and Leslie W.-M. Fung || **

From the Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, Illinois 60607, Department of Biochemistry and Molecular Biology, University of Illinois, Chicago, Illinois 60612, ^|| Department of Chemistry, Loyola University of Chicago, Chicago, Illinois 60626

We have determined the solution NMR structure of a recombinant peptide that consists of the first 156 residues of erythroid -spectrin. The first 20 residues preceding the first helix (helix C') are in a disordered conformation. The subsequent three helices (helices A₁, B₁, and C₁) form a triple helical bundle structural domain that is similar, but not identical, to previously published structures for spectrin from Drosophila and chicken brain. Paramagnetic spin label-induced NMR resonance broadening shows that helix C', the partial domain involved in - and -spectrin association, exhibits little interaction with the structural domain. Surprisingly, helix C' is connected to helix A₁ of the structural domain by a segment of 7 residues (the junction region) that exhibits a flexible disordered conformation, in contrast to the predicted rigid helical structure. We suggest that the flexibility of this particular junction region may play an important role in modulating the association affinity of - and -spectrin at the tetramerization site of different isoforms, such as erythroid spectrin and brain spectrin. These findings may provide insight for explaining various physiological and pathological conditions that are a consequence of varying - and -subunit self-association affinities in their formation of the various spectrin tetramers.

Received for publication, January 20, 2003 , and in revised form, March 31, 2003.

The atomic coordinates and structure factors (code 1OWA) 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 in part by United States National Science Foundation Grants MCB9801870 (to L. W.-M. F.), National Institutes of Health Grant HL57604 (to M. E. J.), American Heart Association Midwest Affiliate Grant 0051630Z (to M. E. J.), and Predoctoral Fellowship 9910169Z (to S. P.). 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.

^¶ To whom correspondence may be addressed: Center for Pharmaceutical Biotechnology, University of Illinois, 900 S. Ashland, Chicago, IL 60607. Tel.: 312-996-9114; E-mail: mjohnson{at}uic.edu. ** To whom correspondence may be addressed: Dept. of Chemistry, Loyola University, 6525 N. Sheridan Rd., Chicago, IL 60626. Tel.: 773-508-3128; E-mail: lfung{at}luc.edu.

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