NACP, A PROTEIN IMPLICATED IN ALZHEIMERS-DISEASE AND LEARNING, IS NATIVELY UNFOLDED

The ''non-A beta component of Alzheimer's disease amyloid plaque'' (NA G) is a minor peptide component of the insoluble fibrillar core of the Alzheimer's disease (AD) neuritic plaque. NAC amyloid fibrils seed th e polymerization of A beta 1-40, the major AD amyloid protein. NAC is derived from a 14 kDa precursor protein, designated NACP, a member of a highly conserved family of heat-stable brain-specific acidic protein s which have been suggested to be involved in synapse formation and/or stabilization. NACP has also been suggested to play a role in AD. We present herein a conformational analysis of human NACP. NACP has a muc h larger Stokes radius (34 Angstrom) but sedimented more slowly (s(20, w) = 1.7S) than globular proteins of similar molecular weight, indicat ing that the native protein is elongated. Circular dichroism (CD) and Fourier-transform infrared spectroscopy (FTIR) indicate the absence of significant amounts of secondary structure in NACP, while CD and ultr aviolet spectroscopy suggest the lack of a hydrophobic core. The confo rmational properties of NACP were unchanged by boiling and were indepe ndent of concentration, pH, salt, and chemical denaturants. These feat ures indicate that NACP exists as a mixture of rapidly equilibrating e xtended conformers and is representative of a class of ''natively unfo lded'' proteins, many of which potentiate protein-protein interactions .