A transient expansion of the native state precedes aggregation of recombinant human interferon-gamma.
A transient expansion of the native state precedes aggregation of recombinant human interferon-gamma.
复制标题
天然状态的短暂扩张先于重组人干扰素-γ的聚集。
DOI：
--
复制
发表时间：
1998
影响因子：
11.1
通讯作者：
T. Randolph
中科院分区：
文献类型：
--
作者：
B. Kendrick;John F. Carpenter;Jeffrey L. Cleland;T. Randolph
Aggregation of proteins, even under conditions favoring the native state, is a ubiquitous problem in biotechnology and biomedical engineering. Providing a mechanistic basis for the pathways that lead to aggregation should allow development of rational approaches for its prevention. We have chosen recombinant human interferon-gamma (rhIFN-gamma) as a model protein for a mechanistic study of aggregation. In the presence of 0.9 M guanidinium hydrochloride, rhIFN-gamma aggregates with first order kinetics, a process that is inhibited by addition of sucrose. We describe a pathway that accounts for both the observed first-order aggregation of rhIFN-gamma and the effect of sucrose. In this pathway, aggregation proceeds through a transient expansion of the native state. Sucrose shifts the equilibrium within the ensemble of rhIFN-gamma native conformations to favor the most compact native species over more expanded ones, thus stabilizing rhIFN-gamma against aggregation. This phenomenon is attributed to the preferential exclusion of sucrose from the protein surface. In addition, kinetic analysis combined with solution thermodynamics shows that only a small (9%) expansion surface area is needed to form the transient native state that precedes aggregation. The approaches used here link thermodynamics and aggregation kinetics to provide a powerful tool for understanding both the pathway of protein aggregation and the rational use of excipients to inhibit the process.
影响因子：
1.6
作者：
Lesley R. Brown;Jing Deng;D. M. Noll;Noriko Mori;Neil D. Clarke
通讯作者：
Lesley R. Brown;Jing Deng;D. M. Noll;Noriko Mori;Neil D. Clarke
影响因子：
2.9
作者：
DEYOUNG, LR;DILL, KA;FINK, AL
通讯作者：
FINK, AL
影响因子：
2.9
作者：
LIU, YF;BOLEN, DW
通讯作者：
BOLEN, DW