ENKAM Pharmaceuticals A/S, Copenhagen, Denmark.
J Neurosci Res. 2010 Aug 1;88(10):2165-76. doi: 10.1002/jnr.22380.
The neural cell adhesion molecule (NCAM) plays a key role in neural development, regeneration, and synaptic plasticity. The crystal structure of a fragment of NCAM comprising the three N-terminal immunoglobulin (Ig)-like modules indicates that the first and second Ig modules bind to each other, thereby presumably mediating dimerization of NCAM molecules expressed on the same cell surface (cis-interactions), whereas the third Ig module, through interactions with the first or second Ig module, mediates interactions between NCAM molecules expressed on the surface of opposing cells (trans-interactions). We have designed a new potent peptide ligand of NCAM, termed plannexin, based on a discontinuous sequence in the second NCAM Ig module that represents a homophilic binding site for an opposing third Ig module. The peptide was found by surface plasmon resonance analysis to bind the third NCAM Ig module. It promoted survival of cultured cerebellar granule neurons (CGNs) and also induced neurite extension in cultures of dopaminergic neurons and CGNs; the latter effect was shown to be dependent on NCAM expression, indicating that plannexin mimics the neuritogenic effect of homophilic NCAM binding.
神经细胞粘附分子（NCAM）在神经发育、再生和突触可塑性中发挥关键作用。NCAM 的一个包含三个 N 端免疫球蛋白（Ig）样模块的片段的晶体结构表明，第一个和第二个 Ig 模块相互结合，从而可能介导在同一细胞表面表达的 NCAM 分子的二聚化（顺式相互作用），而第三个 Ig 模块通过与第一个或第二个 Ig 模块的相互作用，介导在相对细胞表面表达的 NCAM 分子之间的相互作用（反式相互作用）。我们基于 NCAM 第二个 Ig 模块中的不连续序列设计了一种新的 NCAM 有效肽配体，称为 plannexin，它代表了与相反的第三个 Ig 模块的同源结合位点。通过表面等离子体共振分析发现该肽与第三个 NCAM Ig 模块结合。它促进了培养的小脑颗粒神经元（CGN）的存活，并且还诱导多巴胺能神经元和 CGN 培养物中的突起延伸；后一种作用被证明依赖于 NCAM 的表达，表明 plannexin 模拟了同源 NCAM 结合的神经突生成作用。
