biostudies-literaturePantelopulos GAHHS | NIH | Office of Extramural Research, National Institutes of HealthNIA NIH HHSMEXT | RIKENNIGMS NIH HHSe2212207119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9907117biostudies-literatureUnknown119(52)The 99-residue C-terminal domain of amyloid precursor protein (APP-C99), precursor to amyloid beta (A<i>β</i>), is a transmembrane (TM) protein containing intrinsically disordered N- and C-terminal extramembrane domains. Using molecular dynamics (MD) simulations, we show that the structural ensemble of the C99 monomer is best described in terms of thousands of states. The C99 monomer has a propensity to form <i>β</i>-strand in the C-terminal extramembrane domain, which explains the slow spin relaxation times observed in paramagnetic probe NMR experiments. Surprisingly, homodimerization of C99 not only narrows the conformational ensemble from thousands to a few states through the formation of metastable <i>β</i>-strands in extramembrane domains but also stabilizes extramembrane <i>α</i>-helProceedings of the National Academy of Sciences of the United States of AmericaFormation of extramembrane <i>β</i>-strands controls dimerization of transmembrane helices in amyloid precursor protein C99.PMC9907117RO1 GM107703F31 AG061984RF1 AG056147R01 GM107703T32 CA00958229Integrated Lipodology Gylocolipidologue Initiative Dynamic Structure BiologyHutchison JMPantelopulos GASugita YMatsuoka DStraub JEThirumalai DSanders CRfalseFormation of extramembrane <i>β</i>-strands controls dimerization of transmembrane helices in amyloid precursor protein C99.The 99-residue C-terminal domain of amyloid precursor protein (APP-C99), precursor to amyloid beta (A<i>β</i>), is a transmembrane (TM) protein containing intrinsically disordered N- and C-terminal extramembrane domains. Using molecular dynamics (MD) simulations, we show that the structural ensemble of the C99 monomer is best described in terms of thousands of states. The C99 monomer has a propensity to form <i>β</i>-strand in the C-terminal extramembrane domain, which explains the slow spin relaxation times observed in paramagnetic probe NMR experiments. Surprisingly, homodimerization of C99 not only narrows the conformational ensemble from thousands to a few states through the formation of metastable <i>β</i>-strands in extramembrane domains but also stabilizes extramembrane <i>α</i>-hel2022-01-01T00:00:00Z2022 Dec2025-04-22T02:03:37.713Z2025-04-05T20:13:01.394ZS-EPMC99071173653848210.1073/pnas.2212207119