Publication

Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6

Abstract

Herein, we used protein semisynthesis to investigate, for the first time, the effect of lysine acetylation and phosphorylation, as well as the crosstalk between these modifications on the structure and aggregation of mutant huntingtin exon1 (Httex1). Our results demonstrate that phosphorylation at T3 stabilizes the α-helical conformation of the N-terminal 17 amino acids (Nt17) and significantly inhibits the aggregation of mutant Httex1. Acetylation of single lysine residues, K6, K9 or K15, had no effect on Httex1 aggregation. Interestingly, acetylation at K6, but not at K9 or K15, reversed the inhibitory effect of T3 phosphorylation. Together, our results provide novel insight into the role of Nt17 post-translational modifications in regulating the structure and aggregation of Httex1 and suggest that its aggregation and possibly its function(s) are controlled by regulatory mechanisms involving crosstalk between different PTMs.

About this result
This page is automatically generated and may contain information that is not correct, complete, up-to-date, or relevant to your search query. The same applies to every other page on this website. Please make sure to verify the information with EPFL's official sources.
Ontological neighbourhood
Related concepts (23)
Phosphorylation
In biochemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology. Protein phosphorylation often activates (or deactivates) many enzymes. Phosphorylation is essential to the processes of both anaerobic and aerobic respiration, which involve the production of adenosine triphosphate (ATP), the "high-energy" exchange medium in the cell.
Oxidative phosphorylation
Oxidative phosphorylation (UK ɒkˈsɪd.ə.tɪv, US ˈɑːk.sɪˌdeɪ.tɪv ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine triphosphate (ATP). In eukaryotes, this takes place inside mitochondria. Almost all aerobic organisms carry out oxidative phosphorylation. This pathway is so pervasive because it releases more energy than alternative fermentation processes such as anaerobic glycolysis.
Substrate-level phosphorylation
Substrate-level phosphorylation is a metabolism reaction that results in the production of ATP or GTP supported by the energy released from another high-energy bond that leads to phosphorylation of ADP or GDP to ATP or GTP (note that the reaction catalyzed by creatine kinase is not considered as "substrate-level phosphorylation"). This process uses some of the released chemical energy, the Gibbs free energy, to transfer a phosphoryl (PO3) group to ADP or GDP. Occurs in glycolysis and in the citric acid cycle.
Show more
Related publications (34)

Rational combination platform trial design for children and young adults with Diffuse Midline Glioma: a report from PNOC

Sebastian Martin Waszak

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor unresponsive to hundreds of clinical trials. Approximately 80% of DMGs harbor H3K27M oncohistones, which reprogram the epigenome to increase the metabolic profile of the tumor cells. We ha ...
2023

Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice

Johan Auwerx, Xiaoxu Li, Jun Yong Kim, Maroun Bou Sleiman

Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Here, Park et al. identify LETMD1 as a mitochondrial matrix protein enriched in brown adipose tissue (BAT) and reveal a crucial ro ...
NATURE PORTFOLIO2023

Role of the cystathionine beta-synthase / H2S pathway in the development of cellular metabolic dysfunction and pseudohypoxia in down syndrome

Theodora Panagaki

Background: Overexpression of the transsulfuration enzyme cystathionine-beta-synthase (CBS), and overproduction of its product, hydrogen sulfide (H2S) are recognized as potential pathogenetic factors in Down syndrome (DS). The purpose of the study was to d ...
ELSEVIER2022
Show more
Related MOOCs (1)
Water quality and the biogeochemical engine
Learn about how the quality of water is a direct result of complex bio-geo-chemical interactions, and about how to use these processes to mitigate water quality issues.