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Structure of APP-C991-99 and Implications for Role of Extra-Membrane Domains in Function and Oligomerization

View ORCID ProfileGeorge A. Pantelopulos, View ORCID ProfileJohn E. Straub, View ORCID ProfileD. Thirumalai, View ORCID ProfileYuji Sugita
doi: https://doi.org/10.1101/257469
George A. Pantelopulos
1Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215-2521, USA
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John E. Straub
1Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215-2521, USA
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D. Thirumalai
2Department of Chemistry, The University of Texas, Austin, Texas 78712-1224, USA
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Yuji Sugita
3Theoretical Molecular Science Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
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Abstract

The 99 amino acid C-terminal fragment of Amyloid Precursor Protein APP-C99 (C99) is cleaved by γ-secretase to form Aβ peptide, which plays a critical role in the etiology of Alzheimer’s Disease (AD). The structure of C99 consists of a single transmembrane domain flanked by intra and intercellular domains. While the structure of the transmembrane domain has been well characterized, little is known about the structure of the flanking domains and their role in C99 processing by γ-secretase. To gain insight into the structure of full-length C99, REMD simulations were performed for monomeric C99 in model membranes of varying thickness. We find equilibrium ensembles of C99 from simulation agree with experimentally-inferred residue insertion depths and protein backbone chemical shifts. In thin membranes, the transmembrane domain structure is correlated with extra-membrane structural states. Mean and variance of the transmembrane and G37G38 hinge angles are found to increase with thinning membrane. The N-terminus of C99 forms β-strands that may seed aggregation of Aβ on the membrane surface, promoting amyloid formation. The N-terminus, which forms α-helices that interact with the nicastrin domain of γ-secretase. The C-terminus of C99 becomes more α-helical as the membrane thickens, forming structures that may be suitable for binding by cytoplasmic proteins, while C-terminal residues essential to cytotoxic function become α-helical as the membrane thins. The heterogeneous but discrete extra-membrane domain states analyzed here open the path to new investigations of the role of C99 structure and membrane in amyloidogenesis.

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  • ↵* E-mail: straub{at}bu.edu

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Posted February 21, 2018.
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Structure of APP-C991-99 and Implications for Role of Extra-Membrane Domains in Function and Oligomerization
George A. Pantelopulos, John E. Straub, D. Thirumalai, Yuji Sugita
bioRxiv 257469; doi: https://doi.org/10.1101/257469
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Structure of APP-C991-99 and Implications for Role of Extra-Membrane Domains in Function and Oligomerization
George A. Pantelopulos, John E. Straub, D. Thirumalai, Yuji Sugita
bioRxiv 257469; doi: https://doi.org/10.1101/257469

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