The Alzheimers Enzyme’s “Chopstick Capture” Approach

The enzyme responsible for forming amyloid-β plaques recognizes its substrates with two regions that act like a pair of chopsticks, study says.

AsianScientist (Feb. 27, 2015) – The γ-secretase subunit presenilin binds to specific substrates through the cooperation of two regions which act like a pair of chopsticks. This finding, published in the Journal of Neuroscience, could lead to anti-Alzheimer’s drugs with fewer harmful side effects.

Alzheimer’s disease is the most common form of dementia and is thought to be caused by plaques created by the massive deposition of aggregation-prone amyloid-β peptide. Scientists have tried to treat Alzheimer’s by inhibiting γ-secretase, an enzyme known to be involved in the formation of amyloid-β plaques. However, because γ-secretase is also involved in cleaving other proteins, this approach has severe side effects.

In the present study, researchers lead by Professor Taisuke Tomita and former graduate students Shizuka Takagi-Niidome and Tomoki Sasaki at the University of Tokyo, revealed the mechanism by which a catalytic subunit of γ-secretase—called presenilin—captures its substrate. They identified that hydrophilic loop 1 and the carboxy terminus of presenilin are cooperatively involved in capturing the extracellular region of the substrate in a similar fashion to chopsticks.

This is the first report to identify the molecular domains involved in substrate capture during γ-secretase-mediated proteolysis (protein cleavage). These findings could lead to the development of anti-Alzheimer treatments that selectively inhibit Aβ production without adverse side effects.

The article can be found at: Takagi-Niidome et al. (2015) Cooperative Roles of Hydrophilic Loop 1 and the C-Terminus of Presenilin 1 in the Substrate-Gating Mechanism of γ-Secretase.


Source: University of Tokyo.
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