暂时的域间相互作用调节了亨廷丁外子1的单体结构组合和自我组合
Priyesh Mohanty1, Tien Minh Phan1, Jeetain Mittal1,2,3
1Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA.
bioRxiv : the preprint server for biology
|May 20, 2024
概括
亨廷丁外基1 (Httex1) 中的域交叉交谈会影响其聚合. 域间相互作用和多重胺扩张促进有毒构造,导致亨廷顿病的病理学.
科学领域:
- 生物化学和分子生物学
- 神经科学和神经退行性疾病
背景情况:
- 亨廷顿氏病是由亨廷丁元1 (Httex1) 中的多重胺扩张引起的,形成了核内含物.
- Httex1的N-终端N17域自我结合,促进可溶性寡合体的形成,并将多重胺 (polyQ) 导管聚集在一起.
研究的目的:
- 研究Httex1形态组合和寡合化中的结构转换和域交叉交谈之间的相互作用.
- 阐明可溶性Httex1寡合物的转化成不溶性聚合物的机制.
主要方法:
- 广泛的原子分子动力学 (MD) 模拟 (总时间 ~ 0.7 ms).
- 针对C NMR化学转移的MD衍生组合的验证.
- 分析领域间的相互作用和特定领域的结构变化.
主要成果:
- 聚Q扩张增加了α-状性,并有利于短暂的,域间N17-聚Q相互作用,促进β-表形状.
- 域间相互作用与polyQ α-helicity竞争,调节N17介导的二元稳定性,并创造一个异质的二元化景观.
- 富含的C端子域 (PRD) 促进Httex1的凝聚,并通过相互作用抑制N17α-helicity.
结论:
- 域交叉交谈显著调节Httex1单体结构和自我组装.
- N17,polyQ和PRD域之间的相互作用对Httex1聚合和亨廷顿病的发病过程至关重要.
相关概念视频
Protein Complex Assembly
10.6K
Proteins can form homomeric complexes with another unit of the same protein or heteromeric complexes with different types. Most protein complexes self-assemble spontaneously via ordered pathways, while some proteins need assembly factors that guide their proper assembly. Despite the crowded intracellular environment, proteins usually interact with their correct partners and form functional complexes.
Many viruses self-assemble into a fully functional unit using the infected host cell to...
Many viruses self-assemble into a fully functional unit using the infected host cell to...
10.6K
Intrinsically Disordered Proteins
17.8K
Intrinsically disordered proteins are a group of proteins that do not fold into specific three-dimensional structures. Their structural flexibility allows them to complement ordered proteins to perform functions that are inaccessible to rigid structures. They are more common in eukaryotes than prokaryotes and may either be exclusively intrinsically disordered or hybrid proteins, consisting of a mix of ordered and disordered regions. The absence of a rigid structure in these proteins can be...
17.8K
Energy to Drive Translocation
2.1K
Mitochondrial protein import is powered by two distinct energy sources: ATP hydrolysis and electrochemical potential across the inner membrane. Newly synthesized precursors are bound by cytosolic chaperones of the Hsp70 family, which guide them to the import receptors on the mitochondrial surface. Utilizing the energy of ATP hydrolysis, Hsp70 chaperones transfer these precursors to the TOM receptors on the mitochondrial outer membrane.
Generally, polypeptides are unfolded by two distinct...
Generally, polypeptides are unfolded by two distinct...
2.1K
Assembly of Signaling Complexes
5.7K
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
5.7K
Exon Recombination
3.6K
The evolution of new genes is critical for speciation. Exon recombination, also known as exon shuffling or domain shuffling, is an important means of new gene formation. It is observed across vertebrates, invertebrates, and in some plants such as potatoes and sunflowers. During exon recombination, exons from the same or different genes recombine and produce new exon-intron combinations, which might evolve into new genes.
Exon shuffling follows “splice frame rules.” Each exon...
Exon shuffling follows “splice frame rules.” Each exon...
3.6K
Translocation of Proteins into the Mitochondria
3.1K
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
3.1K


