Aggregates of α-chymotrypsinogen anneal to access more stable states.
Aggregates of α-chymotrypsinogen anneal to access more stable states.
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DOI：
10.1002/bit.25129
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发表时间：
2014-04
影响因子：
3.8
通讯作者：
Roberts, Christopher J.
中科院分区：
文献类型：
--
作者：
Maurer, Ronald W.;Hunter, Alan K.;Robinson, Anne S.;Roberts, Christopher J.
非天然蛋白质聚集体在基础和应用生物化学和生物技术中存在各种问题，从药物开发中的质量和安全问题到它们与许多慢性疾病的关联。除了在高度变性条件下，聚集的（通常是淀粉样蛋白）蛋白质状态通常被认为比（部分）未折叠或折叠的单体更稳定和动力学稳定。然而，聚集态的结构和稳定性的演化受到的关注要少得多。本文显示，在轻度变性条件下（高温或[尿素]），与未折叠状态（U）相比，天然单体（N）略微有利，α-胰凝乳蛋白酶原A（aCgn）非天然聚集体经历结构松弛或退火过程，达到更稳定的状态。退火的聚集体比不经历这种松弛过程的聚集体更耐解离。没有退火的聚集体通过线性链解聚解离，并且在促进缓慢解离的条件下（部分变性条件）加速退火。这与具有多个障碍和局部最小值的自由能景观一致，该自由能景观允许聚集体解离和结构弛豫之间的动力学竞争以获得更稳定的聚集体状态。这突出了蛋白质重折叠或聚集体解离过程的复杂性，并可以解释为什么通常难以从聚集体中完全回收单体蛋白质。
Non-native protein aggregates present a variety of problems in fundamental and applied biochemistry and biotechnology, from quality and safety issues in pharmaceutical development to their association with a number of chronic diseases. The aggregated, often amyloid, protein state is often considered to be more thermodynamically and kinetically stable than (partially) unfolded or folded monomers except under highly denaturing conditions. However, evolution of the structure and stability of aggregated states has received much less attention. Here it is shown that under mildly-denaturing conditions (elevated temperature or [urea]), where the native monomer (N) is slightly favored compared to the unfolded state (U), α-chymotrypsinogen A (aCgn) non-native aggregates undergo a structural relaxation or annealing process to reach even more stable states. The annealed aggregates are more resistant to dissociation than aggregates that do not undergo this relaxation process. Aggregates without annealing dissociate via linear chain depolymerization, and annealing is accelerated under conditions that promote slow dissociation (partially denaturing conditions). This is consistent with a free energy landscape with multiple barriers and local minima that allows for a kinetic competition between aggregate dissociation and structural relaxation to more stable aggregate states. This highlights added complexities for protein refolding or aggregate dissociation processes, and may explain why it is often difficult to completely recover monomeric protein from aggregates.
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影响因子：
3.3
作者：
Andrews, Jennifer M.;Roberts, Christopher J.
通讯作者：
Roberts, Christopher J.
影响因子：
3.7
作者：
Hawe, Andrea;Sutter, Marc;Jiskoot, Wim
通讯作者：
Jiskoot, Wim
影响因子：
3.8
作者：
Brummitt, Rebecca K.;Andrews, Jennifer M.;Roberts, Christopher J.
通讯作者：
Roberts, Christopher J.
影响因子：
1.6
作者：
Dobson, CM
通讯作者：
Dobson, CM
DOI：
10.1073/pnas.142459399
发表时间：
2002-07-09
影响因子：
11.1
作者：
Jimenez, JL;Nettleton, EJ;Saibil, HR
通讯作者：
Saibil, HR