第44回 ExCELLSセミナーを開催いたします。
※本セミナーは英語で実施されます。Seminar Language: English
日時
2024年 12月 3日（火） 16:00〜17:00
会場
山手3号館2F西 大会議室
演者
Dr. Janet Kumita
MRC Career Development Award Fellow
Dept. of Pharmacology, University of Cambridge
題目
Designing tuneable synthetic biomolecular condensates to facilitate protein degradation
要旨
With the world’s population ageing, neurodegenerative diseases are a major health concern. This includes Parkinson’s disease (PD), where pathological consequences are directly linked to the formation and deposition of proteinaceous amyloid aggregates composed of α-synuclein. Although there is an intense focus on developing strategies to inhibit the toxic species formed during the process of amyloid formation, disease-modifying therapies have yet to be approved for clinical use. One main difficulty arises from the intricate aggregation pathway, where proteins undergo multiple diverse and ever-changing conformations over time. My research group aims to develop therapeutic strategies to combat the pathological consequences of the amyloid cascade. One aspect we are exploring is whether we can use the cell’s normal quality control mechanisms to target the amyloid cascade – specifically, can we target degradation of disease-related proteins to autophagy, the cell’s waste disposal machinery. Of particular interest is the cell’s ability to rapidly partition biomolecules into membraneless organelles called biomolecular condensates which has been shown to increase Nature’s efficiency within this protein degradation pathway. We are therefore creating engineered biomolecular condensates that will be recruited to the autophagy pathway. Using a phase-separating, consensus-designed tetratricopeptide repeat (CTPR) protein system, we can make precise and predictable rational design changes to the CTPR domain that tunes the condensate propensity1. The system allows us to incorporate peptide motifs to specifically recruit LC3, a key protein involved in the autophagy-lysosome degradation pathway. We are exploring the properties of this system using a combination of in silico modelling, in vitro experiments and cell-based models to define a structure-function relationship between their physicochemical properties and their ability to target degradation via autophagy in the complex cellular environment. Ultimately, we hope that this understanding may lead to the development of designer condensates that can bind to disease-related proteins for targeted protein degradation.
1Ng TLC, Hoare MP, Maristany MJ et al. LS Itzhaki, JR Kumita (2024) bioRxiv doi.org/10.1101/2024.04.16.589709
ポスター
お問い合わせ先
矢木真穂、加藤晃一（生命分子動秩序創発研究グループ）
当日の様子
