8ORY

Solution NMR structure of Notch1 L1740-1743 TMD

8ORY の概要

• エントリーDOI: 10.2210/pdb8ory/pdb
• NMR情報: BMRB: 34806
• 分子名称: Notch 1 extracellular truncation (1 entity in total)
• 機能のキーワード: notch1 l1740-1743, gamma secretase, transmembrane, 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: 3533.57

構造登録者

Guschtschin-Schmidt, N.,Muhle-Goll, C. (登録日: 2023-04-17, 公開日: 2023-08-16, 最終更新日: 2023-08-23)

主引用文献

Ortner, M.,Guschtschin-Schmidt, N.,Stelzer, W.,Muhle-Goll, C.,Langosch, D.
Permissive Conformations of a Transmembrane Helix Allow Intramembrane Proteolysis by gamma-Secretase.
J.Mol.Biol., 435:168218-168218, 2023

PubMed Abstract: The intramembrane protease γ-secretase activates important signaling molecules, such as Notch receptors. It is still unclear, however, how different elements within the primary structure of substrate transmembrane domains (TMDs) contribute to their cleavability. Using a newly developed yeast-based cleavage assay, we identified three crucial regions within the TMDs of the paralogs Notch1 and Notch3 by mutational and gain-of-function approaches. The AAAA or AGAV motifs within the N-terminal half of the TMDs were found to confer strong conformational flexibility to these TMD helices, as determined by mutagenesis coupled to deuterium/hydrogen exchange. Crucial amino acids within the C-terminal half may support substrate docking into the catalytic cleft of presenilin, the enzymatic subunit of γ-secretase. Further, residues close to the C-termini of the TMDs may stabilize a tripartite β-sheet in the substrate/enzyme complex. NMR structures reveal different extents of helix bending as well as an ability to adopt widely differing conformational substates, depending on the sequence of the N-terminal half. The difference in cleavability between Notch1 and Notch3 TMDs is jointly determined by the conformational repertoires of the TMD helices and the sequences of the C-terminal half, as suggested by mutagenesis and building molecular models. In sum, cleavability of a γ-secretase substrate is enabled by different functions of cooperating TMD regions, which deepens our mechanistic understanding of substrate/non-substrate discrimination in intramembrane proteolysis.

PubMed: 37536392
DOI: 10.1016/j.jmb.2023.168218

実験手法

SOLUTION NMR