Implications on zinc binding to S100A2

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• 作者：Michael Koch ; Shibani Bhattacharya ; Torsten Kehl ; Mario Gimona ; Milan Va&#x161 ; á ; k ; Walter Chazin ; Claus W. Heizmann ; Peter M.H. Kroneck ; Gü ; nter Fritz
• 关键词：S100 ; S100A2 ; Zinc ; Calcium ; Cobalt
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：2007
• 期刊代码：20_01674889
• 类别：bio
• 出版时间：March 2007
• 卷：1773
• 期：3
• 页码：457-470
• 文件大小：1051 K

摘要

Human S100A2 is an EF-hand calcium-binding S100 protein that is localized mainly in the nucleus and functions as tumor suppressor. In addition to Ca²⁺ S100A2 binds Zn²⁺ with a high affinity. Studies have been carried out to investigate whether Zn²⁺ acts as a regulatory ion for S100A2, as in the case of Ca²⁺. Using the method of competition with the Zn²⁺ chelator 4-(2-pyridylazo)-resorcinol, an apparent K_d of 25 nM has been determined for Zn²⁺ binding to S100A2. The affinity lies close to the range of intracellular free Zn²⁺ concentrations, suggesting that S100A2 is able to bind Zn²⁺ in the nucleus. Two Zn²⁺-binding sites have been identified using site directed mutagenesis and several spectroscopic techniques with Cd²⁺ and Co²⁺ as probes. In site 1 Zn²⁺ is bound by Cys21 and most likely by His 17. The binding of Zn²⁺ in site 2 induces the formation of a tetramer, whereby the Zn²⁺ is coordinated by Cys2 from each subunit. Remarkably, only binding of Zn²⁺ to site 2 substantially weakens the affinity of S100A2 for Ca²⁺. Analysis of the individual Ca²⁺-binding constants revealed that the Ca²⁺ affinity of one EF-hand is decreased about 3-fold, whereas the other EF-hand exhibits a 300-fold decrease in affinity. These findings imply that S100A2 is regulated by both Zn²⁺ and Ca²⁺, and suggest that Zn²⁺ might deactivate S100A2 by inhibiting response to intracellular Ca²⁺ signals.