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Published online before print September 25, 2006, 10.1110/ps.062154306
Protein Science (2006), 15:2552-2557. Published by Cold Spring Harbor Laboratory Press. Copyright © 2006 The Protein Society
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NMR characterizations of an amyloidogenic conformational ensemble of the PI3K SH3 domain

Hee-Chul Ahn1, Yen T.H. Le2, Partha S. Nagchowdhuri2, Eugene F. DeRose3, Cindy Putnam-Evans4, Robert E. London3, John L. Markley1, and Kwang Hun Lim2

1 Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706-1544, USA
2 Department of Chemistry, East Carolina University, Greenville, North Carolina 27858, USA
3 Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA
4 Department of Biology, East Carolina University, Greenville, North Carolina 27858, USA

(RECEIVED February 15, 2006; FINAL REVISION July 6, 2006; ACCEPTED August 10, 2006)

Amyloid formation is associated with structural changes of native polypeptides to monomeric intermediate states and their self-assembly into insoluble aggregates. Characterizations of the amyloidogenic intermediate state are, therefore, of great importance in understanding the early stage of amyloidogenesis. Here, we present NMR investigations of the structural and dynamic properties of the acid-unfolded amyloidogenic intermediate state of the phosphatidylinositol 3-kinase (PI3K) SH3 domain—a model peptide. The monomeric amyloidogenic state of the SH3 domain studied at pH 2.0 (35°C) was shown to be substantially disordered with no secondary structural preferences. 15N NMR relaxation experiments indicated that the unfolded polypeptide is highly flexible on a subnanosecond timescale when observed under the amyloidogenic condition (pH 2.0, 35°C). However, more restricted motions were detected in residues located primarily in the beta-strands as well as in a loop in the native fold. In addition, nonnative long-range interactions were observed between the residues with the reduced flexibility by paramagnetic relaxation enhancement (PRE) experiments. These indicate that the acid-unfolded state of the SH3 domain adopts a partly folded conformation through nonnative long-range contacts between the dynamically restricted residues at the amyloid-forming condition.

Keywords: amyloids; PI3K SH3; NMR; dynamics; amyloidogenic intermediate; long-range interactions; PRE


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