绘制硬骨蛋白-LRP4 结合界面图,确定硬骨蛋白环 1 和环 3 中的关键相互作用热点。

IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology FEBS Letters Pub Date : 2024-10-23 DOI:10.1002/1873-3468.15033
Svetlana Katchkovsky, Reut Meiri, Shiran Lacham-Hartman, Yaron Orenstein, Noam Levaot, Niv Papo
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引用次数: 0

摘要

硬骨蛋白(Scl)与低密度脂蛋白受体相关蛋白 4(LRP4)的相互作用通过抑制 Wnt/β-catenin 通路导致骨形成明显减少。为了确定Scl-LRP4结合界面的特征,我们对Scl变体组合库进行了分类,并分离出与LRP4亲和力降低的变体。我们确定了在分选过程中富集的 Scl 单突变变体,并验证了它们对 LRP4 的亲和力降低--这种降低并不是变体二级结构或稳定性发生变化的结果。我们发现,Scl 位置 K75(环 1)和 V136(环 3)是与 LRP4 结合的关键热点。我们的发现为针对这些热点开发促进骨形成的新型治疗策略奠定了基础。
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Mapping the sclerostin-LRP4 binding interface identifies critical interaction hotspots in loops 1 and 3 of sclerostin.

The interaction of sclerostin (Scl) with the low-density lipoprotein receptor-related protein 4 (LRP4) leads to a marked reduction in bone formation by inhibiting the Wnt/β-catenin pathway. To characterize the Scl-LRP4 binding interface, we sorted a combinatorial library of Scl variants and isolated variants with reduced affinity to LRP4. We identified Scl single-mutation variants enriched during the sorting process and verified their reduction in affinity toward LRP4-a reduction that was not a result of changes in the variants' secondary structure or stability. We found that Scl positions K75 (loop 1) and V136 (loop 3) are critical hotspots for binding to LRP4. Our findings establish the foundation for targeting these hotspots for developing novel therapeutic strategies to promote bone formation.

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来源期刊
FEBS Letters
FEBS Letters 生物-生化与分子生物学
CiteScore
7.00
自引率
2.90%
发文量
303
审稿时长
1.0 months
期刊介绍: FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.
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