Yop1 的稳定性和膜曲率生成倾向受其寡聚界面控制。

IF 4.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemical Journal Pub Date : 2024-10-16 DOI:10.1042/BCJ20240190
Anu V Chandran, Daniel Álvarez, Stefano Vanni, Jason R Schnell
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引用次数: 0

摘要

DP1 整体膜蛋白家族可稳定内质网和吞噬细胞中的高膜曲率。人类 DP1 基因 REEP1 的突变与遗传性痉挛性截瘫 31 型和远端遗传性运动神经病有关。四个错义突变映射到一个假定的二聚化界面,但这些突变对 DP1 结构和小管形成的影响尚不清楚。结合模型蛋白 Yop1 的生物物理测量、功能测试和计算建模,我们发现错义突变对 DP1 二聚体结构和体外管化活性有不同的影响,并提供了 DP1 寡聚化对膜曲率稳定作用的机理见解。突变 P71L 和 S75F 降低了二聚体的均一性,导致多分散的寡聚化,削弱了膜弯曲活性,而 A72E 则在亚基之间引入了新的极性相互作用,稳定了 Yop1 二聚体,使其能够形成稳健的小管,但却阻止了更高弯曲度的脂蛋白颗粒的形成。在 A72E 的细胞质环上引入 BRIL 结构域可挽救脂蛋白颗粒的形成,这与高弯曲膜对二聚体平展的要求一致。这些结果表明,DP1 蛋白的膜弯曲活性需要二聚体的稳定性和分子间界面的构象可塑性。
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Yop1 stability and membrane curvature generation propensity are controlled by its oligomerisation interface.

The DP1 family of integral membrane proteins stabilize high membrane curvature in the endoplasmic reticulum and phagophores. Mutations in the human DP1 gene REEP1 are associated with Hereditary Spastic Paraplegia type 31 and distal hereditary motor neuropathy. Four missense mutations map to a putative dimerization interface but the impact of these mutations on DP1 structure and tubule formation are unknown. Combining biophysical measurements, functional assays, and computational modeling in the context of the model protein Yop1, we found that missense mutations have variable effects on DP1 dimer structure and in vitro tubulation activity, and provide mechanistic insights into the role of DP1 oligomerisation on membrane curvature stabilization. Whereas the mutations P71L and S75F decreased dimer homogeneity and led to polydisperse oligomerization and impaired membrane curving activity, A72E introduced new polar interactions between subunits that stabilized the Yop1 dimer and allowed robust tubule formation but prevented formation of more highly-curved lipoprotein particles (LPP). The introduction of a BRIL domain to the cytoplasmic loop of A72E rescued LPP formation, consistent with a requirement for dimer splaying in highly curved membranes. These results suggest that the membrane curving activity of DP1 proteins requires both dimer stability and conformational plasticity at the intermolecular interface.

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来源期刊
Biochemical Journal
Biochemical Journal 生物-生化与分子生物学
CiteScore
8.00
自引率
0.00%
发文量
255
审稿时长
1 months
期刊介绍: Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology. The Journal and its Editorial Board are committed to publishing work that provides a significant advance to current understanding or mechanistic insights; studies that go beyond observational work using in vitro and/or in vivo approaches are welcomed. Painless publishing: All papers undergo a rigorous peer review process; however, the Editorial Board is committed to ensuring that, if revisions are recommended, extra experiments not necessary to the paper will not be asked for. Areas covered in the journal include: Cell biology Chemical biology Energy processes Gene expression and regulation Mechanisms of disease Metabolism Molecular structure and function Plant biology Signalling
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