NACP, A Protein Implicated in Alzheimer's Disease and Learning, Is Natively Unfolded

TLDR

The non‑Aβ component of Alzheimer’s disease (NAC) is a minor peptide in the fibrillar core of neuritic plaques that seeds Aβ1‑40 polymerization and is derived from the heat‑stable brain‑specific acidic protein NACP, which has been implicated in synapse formation and Alzheimer’s disease. The study conducts a conformational analysis of human NACP. Human NACP is a natively unfolded protein with a large Stokes radius and elongated shape, lacking secondary structure and a hydrophobic core, and its conformational properties remain unchanged by boiling, concentration, pH, salt, or denaturants, indicating it exists as a mixture of rapidly equilibrating extended conformers that may facilitate protein‑protein interactions.

Abstract

The "non-A beta component of Alzheimer's disease amyloid plaque" (NAC) is a minor peptide component of the insoluble fibrillar core of the Alzheimer's disease (AD) neuritic plaque. NAC amyloid fibrils seed the 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 proteins 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 much larger Stokes radius (34 A) but sedimented more slowly (s20,w = 1.7S) than globular proteins of similar molecular weight, indicating 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 ultraviolet spectroscopy suggest the lack of a hydrophobic core. The conformational properties of NACP were unchanged by boiling and were independent of concentration, pH, salt, and chemical denaturants. These features indicate that NACP exists as a mixture of rapidly equilibrating extended conformers and is representative of a class of "natively unfolded" proteins, many of which potentiate protein-protein interactions.