Molecular Mechanism of Dream -Presenilin-1 Interactions

Abstract

Downstream Regulatory Element Antagonist Modulator (DREAM), also known as calsenilin or potassium channel interacting protein 3 (KChIP3), interacts with presenilin 1 (PS1) and presenilin 2 (PS2) to promote accumulation of β-amyloid peptide in brain. To understand the molecular mechanism by which DREAM mediates β-amyloid formation, the interactions between calsenilin and presenilin were characterized using steady-state and time-resolved fluorescence anisotropy techniques. In addition, the structural changes in DREAM oligomerization state triggered by presenilin binding were studied. Here, we report the interaction between DREAM and a short segment of PS1 C-terminus (helix-9). The binding of DREAM to helix-9 is calcium dependent. The dissociation constant for Ca2+DREAM:helix-9 complexes was determined to be 0.77 ± 0.03 μM, whereas the Mg2+DREAM:complex helix-9 exhibits lower affinity, Kd = 19.3 ± 0.5 μM. Moreover, association of Ca2+DREAM to helix 9 results in slower depolarization with the rotational correlation time of Ф = 22.5 ± 0.1 ns, which matches w the estimated rotational correlation time for DREAM dimer bound to a helix-9. These results suggest that DREAM binds to presenilin in its dimeric form and the formation of the inter-protein complex in regulated by Ca2+.View Large Image | View Hi-Res Image | Download PowerPoint Slide