S Zhang1, N Casey, J P Lee. 1. Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA.
Abstract
BACKGROUND: . Structure-function studies on the Alzheimer's disease peptide sh w that a central hydrophobic cluster - Abeta(17-21), LVFFA - is a prominent structural feature linked to plaque competence. The origin and stability of this cluster was probed in a 17-residue fragment which includes flanking residues that potentially help stabilize the cluster. RESULTS: After residue substitution, the measurement of pKas, amide exchange rates and other NMR data show that any coulombic interactions between His14 and Glu22 are not required for the stability of the central hydrophobic cluster. In contrast, a single substitution within the cluster disrupts its integrity and causes the largest pKa shift for flanking residues, while increasing the solvent accessibility of the backbone. CONCLUSIONS: The integrity of the structurally dominant cluster relies primarily upon local hydrophobic interactions, rather than on interactions between the sidechains of charged flanking residues. Moreover, the conformational disposition of the cluster affects the pKas of flanking residues, underscoring its structural dominance.
BACKGROUND: . Structure-function studies on the Alzheimer's disease peptide sh w that a central hydrophobic cluster - Abeta(17-21), LVFFA - is a prominent structural feature linked to plaque competence. The origin and stability of this cluster was probed in a 17-residue fragment which includes flanking residues that potentially help stabilize the cluster. RESULTS: After residue substitution, the measurement of pKas, amide exchange rates and other NMR data show that any coulombic interactions between His14 and Glu22 are not required for the stability of the central hydrophobic cluster. In contrast, a single substitution within the cluster disrupts its integrity and causes the largest pKa shift for flanking residues, while increasing the solvent accessibility of the backbone. CONCLUSIONS: The integrity of the structurally dominant cluster relies primarily upon local hydrophobic interactions, rather than on interactions between the sidechains of charged flanking residues. Moreover, the conformational disposition of the cluster affects the pKas of flanking residues, underscoring its structural dominance.
Authors: Mary Griffin Krone; Andrij Baumketner; Summer L Bernstein; Thomas Wyttenbach; Noel D Lazo; David B Teplow; Michael T Bowers; Joan-Emma Shea Journal: J Mol Biol Date: 2008-06-04 Impact factor: 5.469