Dataset Information

Dissecting conformational changes in APP's transmembrane domain linked to ?-efficiency in familial Alzheimer's disease.

ABSTRACT: The mechanism by which familial Alzheimer's disease (FAD) mutations within the transmembrane domain (TMD) of the Amyloid Precursor Protein (APP) affect ?-endoproteolysis is only poorly understood. Thereby, mutations in the cleavage domain reduce ?-efficiency of ?-secretase cleavage and some even shift entry into production lines. Since cleavage occurs within the TMD, a relationship between processing and TMD structure and dynamics seems obvious. Using molecular dynamic simulations, we dissect the dynamic features of wild-type and seven FAD-mutants into local and global components. Mutations consistently enhance hydrogen-bond fluctuations upstream of the ?-cleavage sites but maintain strong helicity there. Dynamic perturbation-response scanning reveals that FAD-mutants target backbone motions utilized in the bound state. Those motions, obscured by large-scale motions in the pre-bound state, provide (i) a dynamic mechanism underlying the proposed coupling between binding and ?-cleavage, (ii) key sites consistent with experimentally determined docking sites, and (iii) the distinction between mutants and wild-type.

SUBMITTER: Gotz A

PROVIDER: S-EPMC6028146 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Dissecting conformational changes in APP's transmembrane domain linked to ε-efficiency in familial Alzheimer's disease.

Götz Alexander A Scharnagl Christina C

PloS one 20180702 7

The mechanism by which familial Alzheimer's disease (FAD) mutations within the transmembrane domain (TMD) of the Amyloid Precursor Protein (APP) affect ε-endoproteolysis is only poorly understood. Thereby, mutations in the cleavage domain reduce ε-efficiency of γ-secretase cleavage and some even shift entry into production lines. Since cleavage occurs within the TMD, a relationship between processing and TMD structure and dynamics seems obvious. Using molecular dynamic simulations, we dissect th ...[more]

PMID: 29966005

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Project description:Changes in protein conformation play key roles in facilitating various biochemical processes, ranging from signaling and phosphorylation to transport and catalysis. While various factors that drive these motions such as environmental changes and binding of small molecules are well understood, specific causative effects on the structural features of the protein due to these conformational changes have not been studied on a large scale. Here, we study protein conformational changes in relation to two key structural metrics: packing efficiency and disorder. Packing has been shown to be crucial for protein stability and function by many protein design and engineering studies. We study changes in packing efficiency during conformational changes, thus extending the analysis from a static context to a dynamic perspective and report some interesting observations. First, we study various proteins that adopt alternate conformations and find that tendencies to show motion and change in packing efficiency are correlated: residues that change their packing efficiency show larger motions. Second, our results suggest that residues that show higher changes in packing during motion are located on the changing interfaces which are formed during these conformational changes. These changing interfaces are slightly different from shear or static interfaces that have been analyzed in previous studies. Third, analysis of packing efficiency changes in the context of secondary structure shows that, as expected, residues buried in helices show the least change in packing efficiency, whereas those embedded in bends are most likely to change packing. Finally, by relating protein disorder to motions, we show that marginally disordered residues which are ordered enough to be crystallized but have sequence patterns indicative of disorder show higher dislocation and a higher change in packing than ordered ones and are located mostly on the changing interfaces. Overall, our results demonstrate that between the two conformations, the cores of the proteins remain mostly intact, whereas the interfaces display the most elasticity, both in terms of disorder and change in packing efficiency. By doing a variety of tests, we also show that our observations are robust to the solvation state of the proteins.

Dataset Information

Dissecting conformational changes in APP's transmembrane domain linked to ?-efficiency in familial Alzheimer's disease.

Publications

Dissecting conformational changes in APP's transmembrane domain linked to ε-efficiency in familial Alzheimer's disease.

Similar Datasets

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