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Conformational variability and intramembrane recognition possibly associated with abnormal cleavage of APP transmembrane domain

P. 299-299.
Urban A., Bocharov E. V., Nadezhdin K., Pavlov K., Shtykova E., Tikhaia E., Volynsky P. E., Efremov R., Arseniev A. S., Bocharova O. V.

Bitopic proteins having only one helical transmembrane (TM) domain are a class of biologically significant membrane proteins, including the type I receptors and amyloid precursor protein (APP), which are involved in regulating the homeostasis of human organism and recognized as substrate by c-secretase. Amyloid Ab-peptides forming plaques in brain during Alzheimer disease (AD) are the products of sequential intramembrane cleavage of APP. A lot of mutations associated with AD familial forms were found in the APP transmembrane (TM) domain and juxtamembrane (JM) regions. We designed highly productive systems of bacterial and cell-free expression and easy purification procedure for 13C/15N-isotope labeled APP JM-TM fragments of different length (corresponding to the sequential cleavage steps of APP) and with several familial AD mutations, as well as the TM fragments of c-secretase. The fragments were solubilized in membrane-mimicking complexes (detergent micelles and lipid bicelles), which allows to acquire proper high-resolution NMR spectra despite low sample
stability and to characterize their structural-dynamic properties. Molecular Dynamics relaxation of obtained NMR structures of the fragments in hydrated explicit lipid bilayers provided a detailed atomistic picture of the intra- and intermolecular interactions within membrane. The mutant APP JM-TM fragments are shown to be promising objects for elaboration the molecular aspects of the abnormal recognition and sequential proteolysis by c-secretase, revealing a straightforward mechanism of the pathogenesis associated with some familial AD mutation as well as with aging.


В книге

Под редакцией: M. Purton. Vol. 9: 44th FEBS Congress, From Molecules to Living Systems, Krakow, Poland, July 6‐11, 2019. Oxford: Wiley, 2019.