Structure of the transmembrane domain of human nicastrin-a component of γ-secretase

• Published in: Scientific reports 2016-01, Vol.6 (1), p.19522-19522, Article 19522
• Main Authors: Li, Yan, Liew, Lynette Sin Yee, Li, Qingxin, Kang, CongBao
• Format: Article
• Language: English
• Subjects: 101/6; 631/535/878/1263; 631/57/2271; Amyloid Precursor Protein Secretases - chemistry; Amyloid Precursor Protein Secretases - metabolism; Humanities and Social Sciences; Humans; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - metabolism; Micelles; Models, Molecular; Molecular Dynamics Simulation; multidisciplinary; Nuclear Magnetic Resonance, Biomolecular; Protein Conformation; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Science
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep19522

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.