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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. This Article Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2006-07-038588v1 109/8/3538    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Johnson, C. P Articles by Discher, D. E Search for Related Content PubMed PubMed Citation Articles by Johnson, C. P Articles by Discher, D. E Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 31, 2006 Accepted December 3, 2006 A pathogenic proline mutation in the linker between spectrin repeats: disease due to spectrin unfolding Colin P Johnson, Gaetani Massimiliano, Vanessa Ortiz, Nishant Bhasin, Sandy Harper, Patrick G Gallagher, David W Speicher, and Dennis E Discher* Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA The Wistar Institute, Philadelphia, PA Department of Medicine, Yale University School of Medicine, New Haven, CT * Corresponding author; email: discher{at}seas.upenn.edu. Pathogenic mutations in and spectrin result in a variety of syndromes including hereditary elliptocytosis (HE), spherocytosis, and pyropoikilocytic anemia. While some mutations clearly lie at sites of interaction such as the sites of spectrin - tetramer formation and directly disrupt spectrin binding, 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 -spectrin's first five spectrin repeats, comparing normal spectrin to a pathogenic linker mutation, Q471P between repeats R4 and R5. Results show that the linker mutation at 37 °C destabilizes a significant fraction of the five-repeat construct whereas the wild-type remains fully folded well above body temperature. In wild-type 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 due to proline mutations in spectrin linkers. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Spectrin unfolding mutations: kinks in the links Luanne L. Peters Blood 2007 109: 3133-3134. [Full Text] [PDF] This article has been cited by other articles: P. R. Stabach, I. Simonovic, M. A. Ranieri, M. S. Aboodi, T. A. Steitz, M. Simonovic, and J. S. Morrow The structure of the ankyrin-binding site of {beta}-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties Blood, May 28, 2009; 113(22): 5377 - 5384. [Abstract] [Full Text] [PDF] N. Mohandas and P. G. Gallagher Red cell membrane: past, present, and future Blood, November 15, 2008; 112(10): 3939 - 3948. [Abstract] [Full Text] [PDF] A. J. Baines Mechanisms of elliptocytosis: significant spectrin substitutions Blood, June 15, 2008; 111(12): 5417 - 5417. [Full Text] [PDF] M. Gaetani, S. Mootien, S. Harper, P. G. Gallagher, and D. W. Speicher Structural and functional effects of hereditary hemolytic anemia-associated point mutations in the alpha spectrin tetramer site Blood, June 15, 2008; 111(12): 5712 - 5720. [Abstract] [Full Text] [PDF] D. T. Mirijanian and G. A. Voth Unique elastic properties of the spectrin tetramer as revealed by multiscale coarse-grained modeling PNAS, January 29, 2008; 105(4): 1204 - 1208. [Abstract] [Full Text] [PDF] C. P. Johnson, H.-Y. Tang, C. Carag, D. W. Speicher, and D. E. Discher Forced Unfolding of Proteins Within Cells Science, August 3, 2007; 317(5838): 663 - 666. [Abstract] [Full Text] [PDF] M. Sotomayor and K. Schulten Single-Molecule Experiments in Vitro and in Silico Science, May 25, 2007; 316(5828): 1144 - 1148. [Abstract] [Full Text] [PDF]

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