Advertisement

Topics

Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer's Disease Mutant of APP.

08:00 EDT 29th March 2019 | BioPortfolio

Summary of "Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer's Disease Mutant of APP."

Cleavage of the amyloid precursor protein's (APP) transmembrane domain (TMD) by γ-secretase is a crucial step in the aetiology of Alzheimer's Disease (AD). Mutations in the APP TMD alter cleavage and lead to familial forms of AD (FAD). The majority of FAD mutations shift the preference of initial cleavage from ε49 to ε48, thus raising the AD-related Aβ42/Aβ40 ratio. The I45T mutation is among the few FAD mutations that do not alter ε-site preference, while it dramatically reduces the efficiency of ε-cleavage. Here, we investigate the impact of the I45T mutation on the backbone dynamics of the substrate TMD. Amide exchange experiments and molecular dynamics simulations in solvent and a lipid bilayer reveal an increased stability of amide hydrogen bonds at the ζ- and γ-cleavage sites. Stiffening of the H-bond network is caused by an additional H-bond between the T45 side chain and the TMD backbone, which alters dynamics within the cleavage domain. In particular, the increased H-bond stability inhibits an upward movement of the ε-sites in the I45T mutant. Thus, an altered presentation of ε-sites to the active site of γ-secretase as a consequence of restricted local flexibility provides a rationale for reduced ε-cleavage efficiency of the I45T mutant.

Affiliation

Journal Details

This article was published in the following journal.

Name: Scientific reports
ISSN: 2045-2322
Pages: 5321

Links

DeepDyve research library

PubMed Articles [20516 Associated PubMed Articles listed on BioPortfolio]

Cleavage of carbon-carbon bonds by radical reactions.

In recent years, radical C-C bond cleavage reactions have been increasingly understood and used to perform transformations that complement traditional ionic processes. However, to date radical C-C bon...

Cobalt-Catalyzed Secondary Alkylation of Arenes and Olefins with Alkyl Ethers through the Cleavage of C(sp)-H and C(sp)-O Bonds.

A novel cobalt-catalyzed C-H alkylation of arenes and olefins is achieved with (pyridin-2-yl)isopropyl amine as an N, N-bidentate directing group. Different linear, branched, and cyclic alkyl ethers w...

Iron-catalyzed oxidative C-C(vinyl) σ-bond cleavage of allylarenes to aryl aldehydes at room temperature with ambient air.

A general and selective iron-catalyzed allylic C-C(vinyl) σ-bond cleavage of allylarenes without the assistance of heteroatoms to give aryl aldehydes is reported. The unstrained carbon-carbon single ...

Benchmark DFT studies on C-CN homolytic cleavage and screening the substitution effect on bond dissociation energy.

Nitriles are important chemical species in organic transformations, material chemistry, and environmental sciences. Nitriles are used as cyanating reagents in many organic reactions, where the C-CN bo...

Interactions in the active site of Deinococcus radiodurans RNA polymerase during RNA proofreading.

Co-transcriptional RNA proofreading by RNA polymerase (RNAP) is essential for accurate mRNA synthesis and reactivation of stalled transcription complexes, which can otherwise compromise genome integri...

Clinical Trials [5087 Associated Clinical Trials listed on BioPortfolio]

Validation of Brief Objective Neurobehavioral Detectors (BOND) in Mild TBI

The Veterans Health Administration (VHA) has stated the need for a brief screening instrument that can assist with the triage of the enormous number of returning OEF/OIF veterans with conc...

The Clinical Outcomes Following Transfer of Blastocysts Cultured From Thawed Cleavage Stage Embryos

Recent improvements in cell culture systems have led to a shift in in vitro fertilization (IVF) practice from early cleavage stage embryo transfer (ET) to blastocyst transfer. Blastocyst c...

Clinical Evaluation of Three Dental Adhesive Systems in Class V Restorations

The purpose of this study is to compare the clinical performance of three dental adhesive systems used to bond Class V cavity fillings in adult teeth.

CMC I Stability Intraoperative

The goal of the current study is to objectively measure intraoperative the initial thumb stability after trapezium removal when performing trapeziectomy, alone or in combination with suspe...

Pilot Study of the Best Transfer Strategy in an Oocyte Donation Programme: an Intention to Treat Randomized Controlled Trial

It has been previously shown that even activation of the embryonic genome can begin as early as two days of initiation of the embryonic development (D2), it usually get expressed on day 3 ...

Medical and Biotech [MESH] Definitions

Inorganic or organic derivatives of phosphonic acid with the general formula ROP(OH)2 or RP(=O)(OH)2. The tautomeric form of this compound (P(OH)3) is PHOSPHOROUS ACIDS. Nucleoside phosphonates have a phosphate-carbon bond that is more resistant to enzymatic cleavage than the normal phosphate-oxygen bond.

Chemical bond cleavage reactions resulting from absorption of radiant energy.

A RNA-binding protein that stimulates the cleavage of the 3' end of MRNA near the POLYADENYLATION site. It is a heterotrimer of 55-, 64- and 77-kDa subunits and combines with CLEAVAGE STIMULATION FACTOR to form a stable complex with mRNA that directs the 3' cleavage and polyadenylation reaction.

Enzymes that catalyze the cleavage of a carbon-carbon bond of a 3-hydroxy acid. (Dorland, 28th ed) EC 4.1.3.

Enzymes that catalyze the cleavage of a carbon-oxygen bond by means other than hydrolysis or oxidation. EC 4.2.

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Relevant Topics

Neurology - Central Nervous System (CNS)
Alzheimer's Disease Anesthesia Anxiety Disorders Autism Bipolar Disorders Dementia Epilepsy Multiple Sclerosis (MS) Neurology Pain Parkinson's Disease Sleep Disorders Neurology is the branch of me...

Alzheimer's Disease
Of all the types of Dementia, Alzheimer's disease is the most common, affecting around 465,000 people in the UK. Neurons in the brain die, becuase  'plaques' and 'tangles' (mis-folded proteins) form in the brain. People with Al...

Nutrition
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...


Searches Linking to this Article