H2020Индивидуална стипендия2022–2024

DEEPCONSTRUCT · Understanding epigenetic inheritance and the structures of non-amyloid prion condensates using deep mutagenesis scans

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

Период: 2022-08-01 → 2024-07-31
Финансиране от ЕС: 160 932 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Мутациите в човешките протеини се анализират, за да се разбере как промените в тяхната структура водят до генетични заболявания. Тези данни помагат за по-точна диагностика и разработване на методи за лечение.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Understanding epigenetic inheritance and the structures of non-amyloid prion condensates using deep mutagenesis scans

Proteins are essential molecules that perform a vast array of functions within living organisms. They are made up of long chains of amino acids, which fold into specific three-dimensional structures that determine their function. The relationship between sequence, structure, and function is a central theme in biology. Understanding how a specific sequence leads to a particular function is a complex challenge because even small changes in the sequence (mutations) can significantly alter the protein's behavior. Indeed, mutations in proteins can lead to disease through different mechanisms such as destabilization of the protein fold, by affecting the specific function of the protein, or by causing the protein to aggregate. Predicting the effects of these mutations, or variants, is crucial for understanding their potential impact on health. Accurate predictions can aid in diagnosing genetic disorders, developing treatments, and understanding the underlying mechanisms of disease. In order to improve our understanding of how mutations lead to genetic diseases we set the following objectives: - Generate a large dataset of how mutations in human proteins involved in genetic diseases affect the stability of their three-dimensional folds - Identify which mutations cause genetic diseases through protein destabilization, and analyze the importance of destabilization as a disease mechanism across different diseases and proteins - Use the data to develop predictive models of how mutations affect protein stability to cover a larger number of pathogenic mutations

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

Цел на проекта

Intrinsically disordered regions (IDRs) are pervasive in eukaryotic proteomes despite their poor evolutionary conservation. IDRs have recently gained considerable interest as drivers of the formation of biomolecular condensates, representing a novel fundamental principle of eukaryotic subcellular organization. However, a detailed mechanistic description of how intra and intermolecular interactions drive the formation, stability and physical properties of condensates is lacking.In this project, we will apply deep mutagenesis scans (DMS) to gain insight into sequence-function relationships of IDRs using the remarkable yeast [SMAUG+] non-amyloid prion as a model system. [SMAUG+] is induced through transient overexpression of the RNA binding protein Vts1, leading to the formation of gel-like condensates that are epigenetically inherited through cell divisions. In addition, [SMAUG+] condensates can act as protein-based infectious agents that transform naïve cells. We propose to massively mutagenize Vts1 IDRs and measure the individual and combinatorial effects of IDR mutations on [SMAUG+] formation and stability. This will allow us to gain insight into the mechanisms of condensate formation and prionogenic activity of [SMAUG+], and potentially uncover the structures of condensed [SMAUG+] through analysis of the genetic interactions (epistasis) between mutations. Finally, we will use automated microscopy of selected mutants to understand how mutations affect the inheritance of the prion.The insights obtained from this DMS analysis will be combined with information from previous genome-wide prion formation assays in order to build predictive models of non-amyloid prionogenic activity from protein sequence. The ultimate goal is to translate these models into metazoan proteomes, including human, in order to define novel non-amyloid prion candidates and begin to characterize their functions in non-genetic protein-based inheritance in normal development and in disease.

Оригинален текст от CORDIS (на английски).

Участници

FUNDACIO CENTRE DE REGULACIO GENOMICA · BarcelonaКоординаторИспания