Comparing the folding landscapes of evolutionarily divergent procaspase-3.
Comparing the folding landscapes of evolutionarily divergent procaspase-3.
复制标题
比较进化上不同的半胱天冬酶原-3的折叠景观。
DOI：
10.1042/bsr20220119
复制
发表时间：
2022-06-30
影响因子：
4
通讯作者：
Clark, Clay
中科院分区：
文献类型：
--
作者：
Yao, Liqi;Clark, Clay
所有的半胱天冬酶都从一个共同的祖先进化而来，随后发展成两大类，炎性半胱天冬酶或凋亡半胱天冬酶。半胱天冬酶-血红蛋白酶折叠在近10亿年的进化中一直是保守的，并用于凋亡半胱天冬酶的单体和二聚体亚家族，分别称为启动子和效应子半胱天冬酶。我们比较了折叠和组装的procaspase-3b从斑马鱼到人类的效应procaspases，以检查折叠景观的保护。尿素诱导的procaspase-3b的平衡折叠/展开显示了最小的三态折叠途径，其中天然二聚体异构化为部分折叠的二聚体中间体，然后展开。在人半胱氨酸天冬氨酸蛋白酶原-3的折叠景观中观察到的部分折叠的单体中间体在斑马鱼半胱氨酸天冬氨酸蛋白酶原-3b中没有很好的分布。通过比较不同物种的效应半胱天冬酶，我们表明，效应半胱天冬酶原二聚体经历了pH依赖性的构象变化，并在折叠景观的构象物种表现出类似的自由能。总之，数据表明，景观的半胱天冬酶-血红蛋白酶折叠是保守的，但它提供了灵活性的物种特异性的稳定或不稳定的折叠中间体，导致稳定性的变化。天然二聚体中常见的pH依赖性构象变化（其产生无酶活性的物质）可能提供用于控制细胞中半胱天冬酶活性的额外（尽管是可逆的）机制。
All caspases evolved from a common ancestor and subsequently developed into two general classes, inflammatory or apoptotic caspases. The caspase-hemoglobinase fold has been conserved throughout nearly one billion years of evolution and is utilized for both the monomeric and dimeric subfamilies of apoptotic caspases, called initiator and effector caspases, respectively. We compared the folding and assembly of procaspase-3b from zebrafish to that of human effector procaspases in order to examine the conservation of the folding landscape. Urea-induced equilibrium folding/unfolding of procaspase-3b showed a minimum three-state folding pathway, where the native dimer isomerizes to a partially folded dimeric intermediate, which then unfolds. A partially folded monomeric intermediate observed in the folding landscape of human procaspase-3 is not well-populated in zebrafish procaspase-3b. By comparing effector caspases from different species, we show that the effector procaspase dimer undergoes a pH-dependent conformational change, and that the conformational species in the folding landscape exhibit similar free energies. Together, the data show that the landscape for the caspase-hemoglobinase fold is conserved, yet it provides flexibility for species-specific stabilization or destabilization of folding intermediates resulting in changes in stability. The common pH-dependent conformational change in the native dimer, which yields an enzymatically inactive species, may provide an additional, albeit reversible, mechanism for controlling caspase activity in the cell.