6Z0H

Structure of TREM2 transmembrane helix K186A variant in DPC micelles

6Z0H の概要

• エントリーDOI: 10.2210/pdb6z0h/pdb
• 関連するPDBエントリー: 6Z0G
• NMR情報: BMRB: 50264
• 分子名称: Triggering receptor expressed on myeloid cells 2 (1 entity in total)
• 機能のキーワード: neurodegeneration, proteolysis, membrane protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 5114.02

構造登録者

Steiner, A.,Schlepkow, K.,Brunner, B.,Steiner, H.,Haass, C.,Hagn, F. (登録日: 2020-05-08, 公開日: 2020-09-16, 最終更新日: 2024-06-19)

主引用文献

Steiner, A.,Schlepckow, K.,Brunner, B.,Steiner, H.,Haass, C.,Hagn, F.
gamma-Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics.
Embo J., 39:e104247-e104247, 2020

PubMed Abstract: Sequence variants of the microglial expressed TREM2 (triggering receptor expressed on myeloid cells 2) are a major risk factor for late onset Alzheimer's disease. TREM2 requires a stable interaction with DAP12 in the membrane to initiate signaling, which is terminated by TREM2 ectodomain shedding and subsequent intramembrane cleavage by γ-secretase. To understand the structural basis for the specificity of the intramembrane cleavage event, we determined the solution structure of the TREM2 transmembrane helix (TMH). Caused by the presence of a charged amino acid in the membrane region, the TREM2-TMH adopts a kinked structure with increased flexibility. Charge removal leads to TMH stabilization and reduced dynamics, similar to its structure in complex with DAP12. Strikingly, these dynamical features match with the site of the initial γ-secretase cleavage event. These data suggest an unprecedented cleavage mechanism by γ-secretase where flexible TMH regions act as key determinants of substrate cleavage specificity.

PubMed: 32830336
DOI: 10.15252/embj.2019104247

実験手法

SOLUTION NMR