Cai T, Morishima K, Takagi-Niidome S, Tominaga A, Tomita T.
Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of γ-Secretase.
J Neurosci. 2019 Oct 23;39(43):8600-8610. Epub 2019 Sep 16
PubMed.
The data generated by Tomita’s group supports the emerging view of a highly flexible and dynamic presenilin (PSEN) structure. Recent structural data has highlighted the conformational flexibility of the transmembrane domain (TMD) 2 of PSEN and uncovered coordinated conformational changes in both the protease and the substrate during the formation of the initial enzyme-substrate complex. The present and previous studies thus indicate that PSEN function likely involves coordinated movements throughout the entire PSEN fold. However, the actual molecular motions and structural strategies underlying γ-secretase catalysis, trimming, and its allosteric modulation remain unclear. The data generated in this report, although not providing direct insight into potential novel strategies for drug development, help us to imagine γ-secretase in action, which is in my view a required initial step on this path.
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K.U.Leuven and V.I.B.
The data generated by Tomita’s group supports the emerging view of a highly flexible and dynamic presenilin (PSEN) structure. Recent structural data has highlighted the conformational flexibility of the transmembrane domain (TMD) 2 of PSEN and uncovered coordinated conformational changes in both the protease and the substrate during the formation of the initial enzyme-substrate complex. The present and previous studies thus indicate that PSEN function likely involves coordinated movements throughout the entire PSEN fold. However, the actual molecular motions and structural strategies underlying γ-secretase catalysis, trimming, and its allosteric modulation remain unclear. The data generated in this report, although not providing direct insight into potential novel strategies for drug development, help us to imagine γ-secretase in action, which is in my view a required initial step on this path.
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