McDonald N Q, Panayotatos N, Hendrickson W A
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
EMBO J. 1995 Jun 15;14(12):2689-99. doi: 10.1002/j.1460-2075.1995.tb07269.x.
Ciliary neurotrophic factor (CNTF) promotes the survival and differentiation of developing motor neurons and is a potential therapeutic for treating neurodegeneration and nerve injury. The crystal structure of human CNTF has been determined at 2.4 A resolution using multi-wavelength anomalous diffraction (MAD) phasing from a single Yb3+ ions. The structure reveals that CNTF is dimeric, with a novel anti-parallel arrangement of the subunits, not previously observed for other cytokines. Each subunit adopts a double crossover four-helix bundle fold, in which two helices contribute to the dimer interface, whilst two different helices show pronounced kinks. Analysis of the electrostatic surface of CNTF identified residues within these kinked helices that may contact the CNTF receptor-alpha. Solution experiments show that CNTF dimerizes at concentrations > 40 microM. Such dimers are likely to be relevant to the storage of CNTF in the peripheral nerve given the high concentrations present in this tissue. However, it is unlikely that they play a role in engaging the three distinct receptor subunits that comprise the CNTF receptor, given the low concentration of extracellular CNTF and its high potency.
睫状神经营养因子（CNTF）可促进发育中的运动神经元的存活和分化，是治疗神经退行性变和神经损伤的一种潜在疗法。利用来自单个Yb3+离子的多波长反常衍射（MAD）相位技术，已确定人CNTF的晶体结构，分辨率为2.4埃。该结构显示CNTF是二聚体，亚基呈新颖的反平行排列，这是其他细胞因子以前未观察到的。每个亚基采用双交叉四螺旋束折叠结构，其中两条螺旋构成二聚体界面，而另外两条不同的螺旋有明显的扭结。对CNTF静电表面的分析确定了这些扭结螺旋内可能与CNTF受体α接触的残基。溶液实验表明，CNTF在浓度>40微摩尔时会二聚化。鉴于该组织中存在的高浓度，这种二聚体可能与CNTF在周围神经中的储存有关。然而，鉴于细胞外CNTF的低浓度及其高效能，它们不太可能在与构成CNTF受体的三个不同受体亚基结合中发挥作用。
