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

Scientific Reports
Yan LiCongBao Kang

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.

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Citations

Aug 28, 2021·Microorganisms·Guilherme Curty LechugaSalvatore Giovanni De-Simone
Sep 29, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jing GuJialin Gao
Dec 18, 2020·Dermatology : International Journal for Clinical and Investigative Dermatology·Zhongshuai WangBaoxi Wang

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Methods Mentioned

BETA
glycosylation
NMR
protein folding

Software Mentioned

XPLOR
PyMOL
NIH
NMRView
TALOSN
MOLMOL
Topspin
NMRPipe
XPLORE
PROCHECK

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