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β-Sheet Structure within the Extracellular Domain of C99 Regulates Amyloidogenic Processing.

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Hu, Yi Kienlen-Campard, Pascal [UCL] Tang, Tzu-Chun Perrin, Florian [UCL] Opsomer, Rémi Octave, Jean-Noël [UCL] Smith, Steven O

Familial mutations in C99 can increase the total level of the soluble Aβ peptides produced by proteolysis, as well as the Aβ42/Aβ40 ratio, both of which are linked to the progression of Alzheimer's disease. We show that the extracellular sequence of C99 forms β-sheet structure upon interaction with membrane bilayers. Mutations that disrupt this structure result in a significant increase in Aβ production and, in specific cases, result in an increase in the amount of Aβ42 relative to Aβ40. Fourier transform infrared and solid-state NMR spectroscopic studies reveal a central β-hairpin within the extracellular sequence comprising Y10-E11-V12 and L17-V18-F19 connected by a loop involving H13-H14-Q15. These results suggest how familial mutations in the extracellular sequence influence C99 processing and provide a structural basis for the development of small molecule modulators that would reduce Aβ production.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2017
Language Anglais
Journal information "Scientific Reports" - Vol. 7, p. 17159 (2017)
Peer reviewed yes
Publisher Nature Publishing Group (London)
issn 2045-2322
e-issn 2045-2322
Publication status Publié
Affiliations UCL - SSS/DDUV/SIGN - Cell signalling
UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
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Bibliographic reference Hu, Yi ; Kienlen-Campard, Pascal ; Tang, Tzu-Chun ; Perrin, Florian ; Opsomer, Rémi ; et. al. β-Sheet Structure within the Extracellular Domain of C99 Regulates Amyloidogenic Processing.. In: Scientific Reports, Vol. 7, p. 17159 (2017)
Permanent URL http://hdl.handle.net/2078.1/191452