Abstract
Nicastrin is the largest component of γ-secretase that is an intramembrane protease important in the development of Alzheimer’s disease. Nicastrin contains a large extracellular domain, a single transmembrane (TM) domain, and a short C-terminus. Its TM domain is important for the γ-secretase complex formation. Here we report nuclear magnetic resonance (NMR) studies of the TM and C-terminal regions of human nicastrin in both sodium dodecyl sulfate (SDS) and dodecylphosphocholine (DPC) micelles. Structural study and dynamic analysis reveal that the TM domain is largely helical and stable under both SDS and DPC micelles with its N-terminal region undergoing intermediate time scale motion. The TM helix contains a hydrophilic patch that is important for TM-TM interactions. The short C-terminus is not structured in solution and a region formed by residues V697-A702 interacts with the membrane, suggesting that these residues may play a role in the γ-secretase complex formation. Our study provides structural insight into the function of the nicastrin TM domain and the C-terminus in γ-secretase complex.
Highlights
Understand their function in γ -secretase complex
An N-terminal histidine-tagged construct of human nicastrin containing the TM domain and C-terminus of human nicastrin was made for structural studies (Fig. 1)
The results demonstrate that the nicastrin contains one helix formed by residues E667 to I691
Summary
Understand their function in γ -secretase complex. As nicastrin contains a single TM and a short C-terminus, we investigated its structure using solution NMR spectroscopy to understand its structure and dynamic in solution. We expressed and purified a construct containing residues A664-Y709 of human nicastrin. This construct includes the TM domain and the short C-terminal region of human nicastrin. We used NMR spectroscopy to characterize its structure in both sodium dodecyl sulfate (SDS) and dodecylphosphocholine (DPC) micelles. The C-terminus is flexible while several residues interact with membrane. The current study provides additional information to understand the structure and function of the TM region and the C-terminus of the human nicastrin
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