title: Structure of the transmembrane domain of human nicastrin-a component of γ-secretase.
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.
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), Singapore, 138669 Singapore.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), Singapore, 138669 Singapore.
authors.forename: Lynette Sin Yee
authors.initials: LS
authors.lastname: Liew
authors.affiliation: Institute of Chemical &Engineering Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, 138669 Singapore.
authors.forename: Qingxin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), Singapore, 138669 Singapore.
authors.forename: CongBao
authors.initials: C
authors.lastname: Kang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D008823:Micelles; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary
chemical_list: D008562:Membrane Glycoproteins; D008823:Micelles; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases