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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3538-3543.
Prepublished online as a Blood First Edition Paper on December 27, 2006; DOI 10.1182/blood-2006-07-038588.
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RED CELLS
Pathogenic proline mutation in the linker between spectrin repeats: disease caused by spectrin unfolding
Colin P. Johnson1,
Massimiliano Gaetani2,
Vanessa Ortiz1,
Nishant Bhasin1,
Sandy Harper2,
Patrick G. Gallagher3,
David W. Speicher2, and
Dennis E. Discher1
1 Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA;
2 Systems Biology Division, The Wistar Institute, Philadelphia, PA;
3 Department of Pediatrics, Yale University School of Medicine, New Haven, CT
Pathogenic mutations in  and ß spectrin result in a variety of syndromes, including hereditary elliptocytosis (HE), hereditary pyropoikilocytosis (HPP), and hereditary spherocytosis (HS). Although some mutations clearly lie at sites of interaction, such as the sites of spectrin -ßtetramer formation, a surprising number of HE-causing mutations have been identified within linker regions between distal spectrin repeats. Here we apply solution structural and single molecule methods to the folding and stability of recombinant proteins consisting of the first 5 spectrin repeats of -spectrin, comparing normal spectrin with a pathogenic linker mutation, Q471P, between repeats R4 and R5. Results show that the linker mutation destabilizes a significant fraction of the 5-repeat construct at 37°C, whereas the WT remains fully folded well above body temperature. In WT protein, helical linkers propagate stability from one repeat to the next, but the mutation disrupts the stabilizing influence of adjacent repeats. The results suggest a molecular mechanism for the high frequency of disease caused by proline mutations in spectrin linkers.
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