Structural basis of Notch recognition by human γ-secretase

Area of Science:

• Structural Biology
• Molecular Mechanisms of Disease
• Neuroscience

Background:

• Aberrant cleavage of the Notch receptor by gamma-secretase is implicated in various cancers.
• The precise mechanism by which gamma-secretase recognizes and binds its substrates, such as Notch, has remained elusive.
• Understanding substrate recognition is crucial for deciphering gamma-secretase function in both physiological and pathological contexts.

Purpose of the Study:

• To determine the high-resolution structure of human gamma-secretase in complex with a Notch substrate fragment.
• To elucidate the molecular interactions governing substrate recognition and binding by gamma-secretase.
• To provide structural insights into the cleavage mechanism and its implications for related substrates like amyloid precursor protein.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to visualize the human gamma-secretase/Notch complex.
• High-resolution structural analysis at 2.7 Å resolution.
• Biochemical assays to confirm the functional significance of observed structural features.

Main Results:

• The transmembrane helix of Notch is cradled by three transmembrane domains of Presenilin 1 (PS1), a core component of gamma-secretase.
• A hybrid β-sheet structure is formed between the Notch fragment's C-terminal β-strand and substrate-induced β-strands within PS1.
• PS1 undergoes significant conformational changes upon substrate binding, indicating an active role in substrate engagement and cleavage.

Conclusions:

• The study reveals the structural basis for gamma-secretase's recognition of the Notch substrate.
• Cleavage occurs at the C-terminal end of the Notch transmembrane helix, facilitated by the hybrid β-sheet.
• These findings have implications for understanding how gamma-secretase interacts with other substrates, including the amyloid precursor protein, and for developing targeted therapeutics.