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Remodeling hydrogen bond interactions results in relaxed specificity of Caspase-3.
Bioscience Reports ( IF 4 ) Pub Date : 2021-01-15 , DOI: 10.1042/bsr20203495
Liqi Yao 1 , Paul Swartz 2 , Paul T Hamilton 3 , A Clay Clark 1
Affiliation  

Caspase enzymes play important roles in apoptosis and inflammation, and the non-identical but overlapping specificity profiles (that is, cleavage recognition sequence) direct cells to different fates. Although all caspases prefer aspartate at the P1 position of the substrate, the caspase-6 subfamily shows preference for valine at the P4 position, while caspase-3 shows preference for aspartate. In comparison to human caspases, caspase-3a from zebrafish has relaxed specificity and demonstrates equal selection for either valine or aspartate at the P4 position. In the context of the caspase-3 conformational landscape, we show that changes in hydrogen bonding near the S3 subsite affect selection of the P4 amino acid. Swapping specificity with caspase-6 requires accessing new conformational space, where each landscape results in optimal binding of DxxD (caspase-3) or VxxD (caspase-6) substrate and simultaneously disfavors binding of the other substrate. Within the context of the caspase-3 conformational landscape, substitutions near the active site result in nearly equal activity against DxxD and VxxD by disrupting a hydrogen bonding network in the substrate binding pocket. The converse substitutions in zebrafish caspase-3a result in increased selection for P4 aspartate over valine. Overall, the data show that the shift in specificity that results in a dual function protease, as in zebrafish caspase-3a, requires fewer amino acid substitutions compared to those required to access new conformational space for swapping substrate specificity, such as between caspases-3 and -6.

中文翻译:

重塑氢键相互作用导致 Caspase-3 的特异性放松。

Caspase 酶在细胞凋亡和炎症中发挥重要作用,不同但重叠的特异性谱(即切割识别序列)引导细胞走向不同的命运。尽管所有 caspase 都偏爱底物 P1 位置的天冬氨酸,但 caspase-6 亚家族在 P4 位置偏爱缬氨酸,而 caspase-3 偏爱天冬氨酸。与人类 caspase 相比,来自斑马鱼的 caspase-3a 具有宽松的特异性,并且在 P4 位置显示出对缬氨酸或天冬氨酸的相同选择。在 caspase-3 构象景观的背景下,我们表明 S3 亚位点附近氢键的变化会影响 P4 氨基酸的选择。与 caspase-6 交换特异性需要访问新的构象空间,其中每个景观导致 DxxD (caspase-3) 或 VxxD (caspase-6) 底物的最佳结合,同时不利于其他底物的结合。在 caspase-3 构象景观的背景下,活性位点附近的替换通过破坏底物结合口袋中的氢键网络,导致对 DxxD 和 VxxD 的活性几乎相等。斑马鱼 caspase-3a 中的相反替换导致对 P4 天冬氨酸的选择超过缬氨酸。总体而言,数据表明,导致双功能蛋白酶的特异性转变,如在斑马鱼 caspase-3a 中,与进入新构象空间以交换底物特异性所需的氨基酸取代相比,需要更少的氨基酸取代,例如在 caspase-3 之间和-6。
更新日期:2021-01-18
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