Rounding Out the Understanding of ACD Toxicity with the Discovery of Cyclic Forms of Actin Oligomers.
Rounding Out the Understanding of ACD Toxicity with the Discovery of Cyclic Forms of Actin Oligomers.
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通过发现肌动蛋白低聚物的环状形式，完善了对ACD毒性的理解。
DOI：
10.3390/ijms22020718
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发表时间：
2021-01-13
影响因子：
5.6
通讯作者：
Kudryashov DS
中科院分区：
文献类型：
--
作者：
Smith H;Pinkerton N;Heisler DB;Kudryashova E;Hall AR;Karch KR;Norris A;Wysocki V;Sotomayor M;Reisler E;Vavylonis D;Kudryashov DS
肌动蛋白是先天性和适应性免疫系统的基本要素，可以帮助细菌病原体的运动和移位，使其成为细菌毒素的有吸引力的靶标。致病性弧菌属和气单胞菌属将肌动蛋白交联结构域（actin cross-linking domain，ACD）毒素递送到宿主细胞的细胞质中，以毒害肌动蛋白调节并迅速诱导细胞变圆。在毒性的早期阶段，ACD将肌动蛋白单体共价交联成寡聚体（AO），所述寡聚体通过多价相互作用结合并有效地抑制几个肌动蛋白组装蛋白家族。在晚期毒性阶段，我们发现线性AOs的末端原体可以通过ACD连接在一起，产生环状AOs。当针对福明和Ena/VASP进行测试时，线性和环状AO表现出相似的抑制潜力，而环状AO的抑制潜力在profilin存在下降低。在粗粒度的分子动力学模拟中，profilin和WH 2-motif肌动蛋白亚基上的结合位点仍然暴露在两种几何形状的建模AO中。因此，我们推测，环状AO的毒性降低是由于它们的构型熵降低。环状AO的特征在于，与线性形式相反，它们不能被拉直以形成细丝（例如，通过丝切蛋白的稳定化），这使得它们不易被宿主细胞中和。
Actin is an essential element of both innate and adaptive immune systems and can aid in motility and translocation of bacterial pathogens, making it an attractive target for bacterial toxins. Pathogenic Vibrio and Aeromonas genera deliver actin cross-linking domain (ACD) toxin into the cytoplasm of the host cell to poison actin regulation and promptly induce cell rounding. At early stages of toxicity, ACD covalently cross-links actin monomers into oligomers (AOs) that bind through multivalent interactions and potently inhibit several families of actin assembly proteins. At advanced toxicity stages, we found that the terminal protomers of linear AOs can get linked together by ACD to produce cyclic AOs. When tested against formins and Ena/VASP, linear and cyclic AOs exhibit similar inhibitory potential, which for the cyclic AOs is reduced in the presence of profilin. In coarse-grained molecular dynamics simulations, profilin and WH2-motif binding sites on actin subunits remain exposed in modeled AOs of both geometries. We speculate, therefore, that the reduced toxicity of cyclic AOs is due to their reduced configurational entropy. A characteristic feature of cyclic AOs is that, in contrast to the linear forms, they cannot be straightened to form filaments (e.g., through stabilization by cofilin), which makes them less susceptible to neutralization by the host cell.
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影响因子：
5.6
作者：
Oztug Durer ZA;Diraviyam K;Sept D;Kudryashov DS;Reisler E
通讯作者：
Reisler E
DOI：
10.1126/science.aab4090
发表时间：
2015-07-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Heisler DB;Kudryashova E;Grinevich DO;Suarez C;Winkelman JD;Birukov KG;Kotha SR;Parinandi NL;Vavylonis D;Kovar DR;Kudryashov DS
通讯作者：
Kudryashov DS
影响因子：
3.4
作者：
Kudryashov, DS;Phillips, M;Reisler, E
通讯作者：
Reisler, E
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P
影响因子：
3
作者：
Bernardi, Rafael C.;Melo, Marcelo C. R.;Schulten, Klaus
通讯作者：
Schulten, Klaus