Diskin Ron, Engelberg David, Livnah Oded
The Wolfson Centre for Applied Structural Biology, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.
J Mol Biol. 2008 Jan 4;375(1):70-9. doi: 10.1016/j.jmb.2007.09.002. Epub 2007 Sep 8.
The p38 mitogen-activated protein (MAP) kinases function as signaling molecules essential for many cellular processes, particularly mediating stress response. The activity of p38 MAP kinases is meticulously regulated to reach the desired cellular phenotype. Several alternative activation and attenuation mechanisms have been characterized recently which include new phosphorylation sites. Here we present the crystal structure of p38 alpha MAP kinase in complex with n-octyl-beta-glucopyranoside detergent. The complex unveils a novel lipid-binding site formed by a local conformational change of the MAP kinase insert. This binding is the first attribution for a possible role of the MAP kinase insert in p38. The binding site can accommodate a large selection of lipidic molecules. In addition, we also show via biophysical methods that arachidonic acid and its derivatives bind p38 alpha in vitro. Based on our analysis we propose that the binding of lipids could fine-tune p38 alpha catalytic activity towards a preferred phenotype.
p38丝裂原活化蛋白（MAP）激酶作为许多细胞过程所必需的信号分子，尤其在介导应激反应中发挥作用。p38 MAP激酶的活性受到精确调控，以实现所需的细胞表型。最近已鉴定出几种替代性激活和衰减机制，其中包括新的磷酸化位点。在此，我们展示了与正辛基-β-D-吡喃葡萄糖苷去污剂形成复合物的p38α MAP激酶的晶体结构。该复合物揭示了一个由MAP激酶插入片段的局部构象变化形成的新型脂质结合位点。这种结合首次归因于MAP激酶插入片段在p38中可能发挥的作用。该结合位点可容纳多种脂质分子。此外，我们还通过生物物理方法表明，花生四烯酸及其衍生物在体外与p38α结合。基于我们的分析，我们提出脂质的结合可能会将p38α催化活性微调至优选的表型。
