| First Author | Yagi H | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 42 | Pages | 25213-26 |
| PubMed ID | 26306037 | Mgi Jnum | J:327044 |
| Mgi Id | MGI:6830380 | Doi | 10.1074/jbc.M115.668384 |
| Citation | Yagi H, et al. (2015) Structural Basis for Ca2+-mediated Interaction of the Perforin C2 Domain with Lipid Membranes. J Biol Chem 290(42):25213-26 |
| abstractText | Natural killer cells and cytotoxic T-lymphocytes deploy perforin and granzymes to kill infected host cells. Perforin, secreted by immune cells, binds target membranes to form pores that deliver pro-apoptotic granzymes into the target cell. A crucial first step in this process is interaction of its C2 domain with target cell membranes, which is a calcium-dependent event. Some aspects of this process are understood, but many molecular details remain unclear. To address this, we investigated the mechanism of Ca(2+) and lipid binding to the C2 domain by NMR spectroscopy and x-ray crystallography. Calcium titrations, together with dodecylphosphocholine micelle experiments, confirmed that multiple Ca(2+) ions bind within the calcium-binding regions, activating perforin with respect to membrane binding. We have also determined the affinities of several of these binding sites and have shown that this interaction causes a significant structural rearrangement in CBR1. Thus, it is proposed that Ca(2+) binding at the weakest affinity site triggers changes in the C2 domain that facilitate its interaction with lipid membranes. |
