The Department of Pharmacology, Yale University, 333 Cedar St., New Haven, CT, 06520, USA.
The Department of Cell Biology, Yale University, 333 Cedar St., New Haven, CT, 06520, USA.
Commun Biol. 2022 Nov 17;5(1):1257. doi: 10.1038/s42003-022-04157-3.
Integrin adhesion receptors provide links between extracellular ligands and cytoplasmic signaling. Multiple kinases have been found to directly engage with integrin β tails, but the molecular basis for these interactions remain unknown. Here, we assess the interaction between the kinase domain of p21-activated kinase 4 (PAK4) and the cytoplasmic tail of integrin β5. We determine three crystal structures of PAK4-β5 integrin complexes and identify the PAK-binding site. This is a region in the membrane-proximal half of the β5 tail and confirmed by site-directed mutagenesis. The β5 tail engages the kinase substrate-binding groove and positions the non-phosphorylatable integrin residue Glu767 at the phosphoacceptor site. Consistent with this, integrin β5 is poorly phosphorylated by PAK4, and in keeping with its ability to occlude the substrate-binding site, weakly inhibits kinase activity. These findings demonstrate the molecular basis for β5 integrin-PAK4 interactions but suggest modifications in understanding the potential cellular role of this interaction.
整合素黏附受体提供细胞外配体和细胞质信号之间的联系。已经发现多种激酶可以直接与整合素β尾部结合，但这些相互作用的分子基础仍然未知。在这里，我们评估了 p21 激活激酶 4（PAK4）的激酶结构域与整合素β5 胞质尾部之间的相互作用。我们确定了 PAK4-β5 整合素复合物的三个晶体结构，并确定了 PAK 结合位点。这是β5 尾部膜近端一半的一个区域，通过定点突变得到证实。β5 尾部与激酶底物结合槽结合，并将非磷酸化的整合素残基 Glu767 定位在磷酸受体位点。与之一致的是，整合素β5 被 PAK4 磷酸化的程度很差，并且与其能够封闭底物结合位点的能力一致，它对激酶活性的抑制作用较弱。这些发现表明了β5 整合素-PAK4 相互作用的分子基础，但表明需要对这种相互作用的潜在细胞作用进行修正理解。
