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Physical tuning of galectin-3 signaling [Biochemistry]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-05-11 , DOI: 10.1073/pnas.2024117118
Shaheen A. Farhadi, Renjie Liu, Matthew W. Becker, Edward A. Phelps, Gregory A. Hudalla

Galectin-3 (Gal3) exhibits dynamic oligomerization and promiscuous binding, which can lead to concomitant activation of synergistic, antagonistic, or noncooperative signaling pathways that alter cell behavior. Conferring signaling pathway selectivity through mutations in the Gal3–glycan binding interface is challenged by the abundance of common carbohydrate types found on many membrane glycoproteins. Here, employing alpha-helical coiled-coils as scaffolds to create synthetic Gal3 constructs with defined valency, we demonstrate that oligomerization can physically regulate extracellular signaling activity of Gal3. Constructs with 2 to 6 Gal3 subunits (“Dimer,” “Trimer,” “Tetramer,” “Pentamer,” “Hexamer”) demonstrated glycan-binding properties and cell death–inducing potency that scaled with valency. Dimer was the minimum functional valency. Unlike wild-type Gal3, which signals apoptosis and mediates agglutination, synthetic Gal3 constructs induced cell death without agglutination. In the presence of CD45, Hexamer was distributed on the cell membrane, whereas it clustered in absence of CD45 via membrane glycans other than those found on CD7. Wild-type Gal3, Pentamer, and Hexamer required CD45 and CD7 to signal apoptosis, and the involvement of caspases in apoptogenic signaling was increased in absence of CD45. However, wild-type Gal3 depended on caspases to signal apoptosis to a greater extent than Hexamer, which had greater caspase dependence than Pentamer. Diminished caspase activation downstream of Hexamer signaling led to decreased pannexin-1 hemichannel opening and interleukin-2 secretion, events facilitated by the increased caspase activation downstream of wild-type Gal3 signaling. Thus, synthetic fixation of Gal3 multivalency can impart physical control of its outside-in signaling activity by governing membrane glycoprotein engagement and, in turn, intracellular pathway activation.



中文翻译:

galectin-3信号传导的物理调节[生物化学]

Galectin-3(Gal3)表现出动态寡聚和混杂结合,可导致协同,拮抗或非合作性信号通路同时激活,从而改变细胞行为。通过在Gal3–聚糖结合界面中发生突变来赋予信号通路选择性,是受到许多膜糖蛋白上常见碳水化合物类型的挑战。在这里,采用α-螺旋线圈作为支架来创建具有确定化合价的合成Gal3构建体,我们证明寡聚可以物理调节Gal3的细胞外信号传导活性。具有2到6个Gal3亚基的构建体(“二聚体”,“三聚体”,“四聚体”,“五聚体”,“六聚体”)表现出聚糖结合特性和诱导细胞死亡的能力,其效价呈比例关系。二聚体是最低功能价。与野生型Gal3发出信号并介导凝集的野生型Gal3不同,合成的Gal3构建体在没有凝集的情况下诱导了细胞死亡。在存在CD45的情况下,六聚体分布在细胞膜上,而在CD45不存在的情况下,六聚体通过CD7以外的膜聚糖聚集。野生型Gal3,Pentamer和Hexamer需要CD45和CD7才能发出细胞凋亡信号,而在没有CD45的情况下,胱天蛋白酶在细胞凋亡信号传导中的作用会增加。但是,野生型Gal3依赖于胱天蛋白酶来在比Hexamer更大的程度上信号传导细胞凋亡,而Hexamer的caspase依赖性比Pentamer大。Hexamer信号传导下游的半胱天冬酶激活减少导致pannexin-1半通道开放和白介素2分泌减少,在野生型Gal3信号传导下游增加的半胱天冬酶激活促进了这些事件。因此,Gal3多价的合成固定可通过控制膜糖蛋白的结合并进而控制细胞内途径的激活,从而对其外向内的信号传导活性进行物理控制。

更新日期:2021-05-03
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