Vogl Thomas, Gharibyan Anna L, Morozova-Roche Ludmilla A
Institute of Immunology, University of Muenster, Röntgenstr. 21, 48149 Muenster, Germany.
Department of Medical Biochemistry and Biophysics, Umea University, SE-901 87 Umea, Sweden.
Int J Mol Sci. 2012;13(3):2893-2917. doi: 10.3390/ijms13032893. Epub 2012 Mar 5.
S100A8 and S100A9 are EF-hand Ca(2+) binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target proteins. S100A8 and S100A9 expression levels increased in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases and they are implicated in the numerous disease pathologies. The Ca(2+) and Zn(2+)-binding properties of S100A8/A9 have a pivotal influence on their conformation and oligomerization state, including self-assembly into homo- and heterodimers, tetramers and larger oligomers. Here we review how the unique chemical and conformational properties of individual proteins and their structural plasticity at the quaternary level account for S100A8/A9 functional diversity. Additional functional diversification occurs via non-covalent assembly into oligomeric and fibrillar amyloid complexes discovered in the aging prostate and reproduced in vitro. This process is also regulated by Ca(2+)and Zn(2+)-binding and effectively competes with the formation of the native complexes. High intrinsic amyloid-forming capacity of S100A8/A9 proteins may lead to their amyloid depositions in numerous ailments characterized by their elevated expression patterns and have additional pathological significance requiring further thorough investigation.
S100A8和S100A9是属于S100家族的EF手型钙结合蛋白。它们在吞噬细胞的胞质溶胶中含量丰富，通过与靶蛋白相互作用并调节其活性，在许多细胞过程中发挥关键作用，如运动和危险信号传导。S100A8和S100A9的表达水平在多种癌症、神经退行性疾病、炎症和自身免疫性疾病中升高，它们与众多疾病病理相关。S100A8/A9的钙结合和锌结合特性对其构象和寡聚化状态具有关键影响，包括自组装成同二聚体、异二聚体、四聚体和更大的寡聚体。在这里，我们综述了单个蛋白质独特的化学和构象特性及其在四级水平的结构可塑性如何解释S100A8/A9的功能多样性。通过非共价组装形成在衰老前列腺中发现并在体外重现的寡聚体和纤维状淀粉样复合物，还会发生额外的功能多样化。这个过程也受钙结合和锌结合的调节，并有效地与天然复合物的形成竞争。S100A8/A9蛋白高的内在淀粉样蛋白形成能力可能导致它们在许多以其表达模式升高为特征的疾病中发生淀粉样蛋白沉积，并具有需要进一步深入研究的额外病理意义。
