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-protein monomer folding
1 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
2 Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA
(RECEIVED December 16, 2004; FINAL REVISION February 18, 2005; ACCEPTED February 18, 2005)
Neurotoxic assemblies of the amyloid 
-protein (A) have been linked strongly to the pathogenesis of Alzheimer’s disease (AD). Here, we sought to monitor the earliest step in A assembly, the creation of a folding nucleus, from which oligomeric and fibrillar assemblies emanate. To do so, limited proteolysis/mass spectrometry was used to identify protease-resistant segments within monomeric A(1–40) and A(1–42). The results revealed a 10-residue, protease-resistant segment, Ala21–Ala30, in both peptides. Remarkably, the homologous decapeptide, A(21–30), displayed identical protease resistance, making it amenable to detailed structural study using solution-state NMR. Structure calculations revealed a turn formed by residues Val24–Lys28. Three factors contribute to the stability of the turn, the intrinsic propensities of the Val-Gly-Ser-Asn and Gly-Ser-Asn-Lys sequences to form a -turn, long-range Coulombic interactions between Lys28 and either Glu22 or Asp23, and hydrophobic interaction between the isopropyl and butyl side chains of Val24 and Lys28, respectively. We postulate that turn formation within the Val24–Lys28 region of A nucleates the intramolecular folding of A monomer, and from this step, subsequent assembly proceeds. This model provides a mechanistic basis for the pathologic effects of amino acid substitutions at Glu22 and Asp23 that are linked to familial forms of AD or cerebral amyloid angiopathy. Our studies also revealed that common C-terminal peptide segments within A(1–40) and A(1–42) have distinct structures, an observation of relevance for understanding the strong disease association of increased A(1–42) production. Our results suggest that therapeutic approaches targeting the Val24–Lys28 turn or the A(1–42)-specific C-terminal fold may hold promise.
Keywords: Alzheimer’s disease; amyloid; amyloid -protein; folding nucleus; protein folding
Abbreviations: A, amyloid-protein • CT, chymotrypsin • DQF-COSY, double-quantum filtered correlation spectroscopy • Asp-N, endoproteinase AspN • GluC, endoproteinase Glu-C • HNE, human neutrophil elastase • NOESY, nuclear Overhauser enhancement spectroscopy • PPE, porcine pancreatic elastase • RP-HPLC, reverse-phase high-performance liquid chromatography • ROESY, rotating-frame Overhauser enhancement spectroscopy • TH, thermolysin • TOCSY, total correlation spectroscopy • TR, trypsin.
Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041292205.
Reprint requests to: David B. Teplow, Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza (Reed C119A), Los Angeles, CA 90095, USA; e-mail: dteplow{at}mednet.ucla.edu; fax: (310) 206-1700.
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