LINKAGE BETWEEN LIGAND-BINDING AND THE DIMER-TETRAMER EQUILIBRIUM IN THE MONOD-WYMAN-CHANGEUX MODEL OF HEMOGLOBIN
LINKAGE BETWEEN LIGAND-BINDING AND THE DIMER-TETRAMER EQUILIBRIUM IN THE MONOD-WYMAN-CHANGEUX MODEL OF HEMOGLOBIN
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DOI：
10.1073/pnas.83.11.3796
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发表时间：
1986-06-01
影响因子：
11.1
通讯作者：
EDSALL, JT
中科院分区：
文献类型：
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作者：
EDELSTEIN, SJ;EDSALL, JT
G. Weber [（1984）Proc.Natl. Acad. Sci. USA 81，7098-7102]已经推断血红蛋白与配体结合的Monod-Wyman-Changeux（MWC）模型将要求（与实验证据相反）增加的配体结合必须促进α 2 β 2四聚体关于解离成α的稳定化。β的二聚体。然而，根据一般联系原则和G。K. Ackers和M. L.约翰逊[（1981）J. Mol. Biol. 147，559-582]表明相反的关系必须保持，与实验一致。具有低配体亲和力的四聚体的T形式必须不稳定，并且随着配体结合的增加而逐渐解离成高亲和力二聚体，称为D。每个结合的配体分子使D-T平衡的标准吉布斯自由能Δ G2 T移动约3 kcal/mol，有利于二聚体。因此，T必须存在于（至少）五个Δ G水平的协同自由能中，因为它通过配体分子的连续结合而逐渐变得不稳定。相反，R四聚体解离成二聚体与结合的配体的量无关，只要二聚体和R状态四聚体对配体具有相同的（高）亲和力。虽然T和R状态（KT和KR）的固有配体结合常数在整个模型的假设下保持不变，但鉴于上述多个自由能级，该模型不应被视为严格的两态系统。目前的分析给出近似的，但不精确的，协议与实验结果的二聚体，四聚体平衡考虑韦伯和解释其他最近的实验有关这种平衡提供了一个合理的解释。
G. Weber [(1984) Proc. Natl. Acad. Sci. USA 81, 7098-7102] had inferred that the Monod-Wyman-Changeux (MWC) model for ligand binding by hemoglobin would require (contrary to experimental evidence) that increased ligand binding must promote stabilization of .alpha.2.beta.2 tetramers with respect to dissociation into .alpha..beta. dimers. Reexamination of the MWC model, however, in the light of general linkage principles and the specific analysis by G. K. Ackers and M. L. Johnson [(1981) J. Mol. Biol. 147, 559-582] shows that the opposite relation must hold, in agreement with experiment. The T form of the tetramer, with low ligand affinity, must be destabilized and progressively dissociates into the high-affinity dimers, designated D, as ligand binding increases. Each ligand molecule bound shifts the standard Gibbs free energy .DELTA.G2T for the D-T equilibrium by approximately 3 kcal/mol in favor the dimer. Thus, T must exist in (at least) five .DELTA.G levels of cooperative free energy as it becomes progressively destabilized by successive binding of ligand molecules. Dissociation of the R tetramer to dimers, in contrast, is independent of the amount of ligand bound, so long as dimers and R-state tetramers possess the same (high) affinity for ligand. While the intrinsic ligand-binding constants of the T and R states (KT and KR) remain unchanged throughout by the postulates of the model, the model should not be regarded as a strictly two-state system in view of the multiple free-energy levels indicated above. The present analysis gives approximate, though not precise, agreement with experimental findings on the dimer-tetramer equilibrium considered by Weber and provides a rationale for interpreting other recent experiments concerning this equilibrium.