Ostendorp Thorsten, Leclerc Estelle, Galichet Arnaud, Koch Michael, Demling Nina, Weigle Bernd, Heizmann Claus W, Kroneck Peter M H, Fritz Günter
Fachbereich Biologie, Mathematisch-Naturwissenschaftliche Sektion, Universität Konstanz, Konstanz, Germany.
EMBO J. 2007 Aug 22;26(16):3868-78. doi: 10.1038/sj.emboj.7601805. Epub 2007 Jul 26.
Nervous system development and plasticity require regulation of cell proliferation, survival, neurite outgrowth and synapse formation by specific extracellular factors. The EF-hand protein S100B is highly expressed in human brain. In the extracellular space, it promotes neurite extension and neuron survival via the receptor RAGE (receptor for advanced glycation end products). The X-ray structure of human Ca(2+)-loaded S100B was determined at 1.9 A resolution. The structure revealed an octameric architecture of four homodimeric units arranged as two tetramers in a tight array. The presence of multimeric forms in human brain extracts was confirmed by size-exclusion experiments. Recombinant tetrameric, hexameric and octameric S100B were purified from Escherichia coli and characterised. Binding studies show that tetrameric S100B binds RAGE with higher affinity than dimeric S100B. Analytical ultracentrifugation studies imply that S100B tetramer binds two RAGE molecules via the V-domain. In line with these experiments, S100B tetramer caused stronger activation of cell growth than S100B dimer and promoted cell survival. The structural and the binding data suggest that tetrameric S100B triggers RAGE activation by receptor dimerisation.
神经系统的发育和可塑性需要特定细胞外因子对细胞增殖、存活、神经突生长和突触形成进行调控。EF手蛋白S100B在人类大脑中高度表达。在细胞外空间，它通过受体RAGE（晚期糖基化终产物受体）促进神经突延伸和神经元存活。人类钙离子负载的S100B的X射线结构在1.9埃分辨率下得以确定。该结构揭示了由四个同二聚体单元组成的八聚体结构，排列成两个紧密排列的四聚体。通过尺寸排阻实验证实了人类脑提取物中存在多聚体形式。从大肠杆菌中纯化并表征了重组四聚体、六聚体和八聚体S100B。结合研究表明，四聚体S100B比二聚体S100B以更高的亲和力结合RAGE。分析超速离心研究表明，S100B四聚体通过V结构域结合两个RAGE分子。与这些实验一致，S100B四聚体比S100B二聚体引起更强的细胞生长激活并促进细胞存活。结构和结合数据表明，四聚体S100B通过受体二聚化触发RAGE激活。
