H2020Индивидуална стипендия2022–2024

SYN-CHARGE · Novel avenues of action for a hallmark disordered protein of Parkinson's disease

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2022-02-01 → 2024-01-31
Финансиране от ЕС: 219 312 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Взаимодействията между протеини без фиксирана структура, като алфа-синуклеинът при болестта на Паркинсон, се анализират чрез използването на техните огледални образи (енантиомери). Това помага за разбирането на начина, по който динамичните протеини се свързват и функционират в клетката.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Novel avenues of action for a hallmark disordered protein of Parkinson's disease

The study of protein-protein interactions is central to protein biochemistry with proteins being the functional workhorse of biological systems. Studying protein structure helps us to understand how proteins function, how they interact and their role within the context of the cellular machinery. A subset of proteins lacks persistent three-dimensional structure and are highly dynamic – the so-called intrinsically disordered proteins (IDPs). Historically, all protein interactions were thought to rely heavily on structure, for example: the interactions of IDPs may induce the formation of structure. This view changed upon the discovery of a high affinity, completely disordered, dynamic interaction characterized by a collaborative effort between the Kragelund, Best and Schuler research groups. The presence of interacting partners that remain disordered upon binding was unexpected, and challenged the ways in which we think about protein interactions. It is possible that more proteins can interact in this way, but researchers have lacked understanding of the ways in which they can be observed. The goal of this research program was to identify a new ways of understanding disorder in protein-protein interactions. Initially we aimed to do this using the interaction between the disordered region of a calcium pump (plasma membrane calcium ATPase) and alpha-synuclein, however upon careful investigation the link between the two proteins was found to be via an indirect mechanism, therefore disqualifying it as a good candidate for this investigation. Instead, we focused on the disorder-order continuum of interactions, substituting one disordered binding partner for its enantiomer. Enantiomers are chemically identical to each other, but are non-superimposable mirror images, meaning that proteins have a “handedness”. We hypothesized that in completely disordered interactions, enantiomers could interact with their binding partner regardless of their handedness, whereas in structured interactions, they could not. In this way, we could test the degree of disorder and reliance on protein charge within a protein-protein interaction.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Alpha-synuclein (aSN) is an intrinsically disordered protein (IDP) expressed by neurons, and well-known to aggregate in so-called Lewy bodies (LB) that are a hallmark of Parkinson’s disease (PD) and other LB disorders. Despite extensive research, the mechanisms underlying its toxicity in these disorders still remains to be understood. In this project, I will determine whether aSN can interact with other disordered proteins in a novel, mean-field type interaction, focusing on the disordered loop of the neuronal plasma membrane Ca2+ ATPase (PMCA). I will study this using biophysical techniques, in particular NMR, ITC and SAXS/SANS. This project will improve the understanding of aSN and its interactions and has the potential to pave the way for new discoveries, especially in drug design. I will gain important experience in project design and management, a research network in Europe, and take a significant step towards independence. I will undertake this project at the University of Copenhagen in the research group of Professor Birthe B. Kragelund, an expert in the field of IDP research. The Kragelund group has recently joined the BRAINSTRUC Consortium: a group of researchers working on the structural characterization of neuronal proteins. Thus, they required a postdoctoral researcher with a strong background in neuroscience and structural biology. I was uniquely qualified to take this position as I have been working on neurodegenerative proteins for several years and structurally characterized the IDP associated with Huntington’s disease. Professor Kragelund has experience supervising productive postdoctoral researchers, an extensive European network, and has access to the state-of-the-art facilities necessary to complete this project. I have recently acquired preliminary data to indicate that the two proteins (aSN and PMCA) interact directly. This project has the potential to change how we understand proteins associated with neurodegeneration and their interactions.

Оригинален текст от CORDIS (на английски).

Участници

KOBENHAVNS UNIVERSITET · KOBENHAVNКоординаторДания