Traore Daouda A K, Brennan Amelia J, Law Ruby H P, Dogovski Con, Perugini Matthew A, Lukoyanova Natalya, Leung Eleanor W W, Norton Raymond S, Lopez Jamie A, Browne Kylie A, Yagita Hideo, Lloyd Gordon J, Ciccone Annette, Verschoor Sandra, Trapani Joseph A, Whisstock James C, Voskoboinik Ilia
††Crystallography, Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, U.K.
Biochem J. 2013 Dec 15;456(3):323-35. doi: 10.1042/BJ20130999.
Following its secretion from cytotoxic lymphocytes into the immune synapse, perforin binds to target cell membranes through its Ca(2+)-dependent C2 domain. Membrane-bound perforin then forms pores that allow passage of pro-apoptopic granzymes into the target cell. In the present study, structural and biochemical studies reveal that Ca(2+) binding triggers a conformational change in the C2 domain that permits four key hydrophobic residues to interact with the plasma membrane. However, in contrast with previous suggestions, these movements and membrane binding do not trigger irreversible conformational changes in the pore-forming MACPF (membrane attack complex/perforin-like) domain, indicating that subsequent monomer-monomer interactions at the membrane surface are required for perforin pore formation.
穿孔素从细胞毒性淋巴细胞分泌到免疫突触后，通过其钙离子依赖的C2结构域与靶细胞膜结合。结合在膜上的穿孔素随后形成孔道，使促凋亡颗粒酶进入靶细胞。在本研究中，结构和生化研究表明，钙离子结合引发C2结构域的构象变化，使四个关键疏水残基与质膜相互作用。然而，与之前的推测相反，这些运动和膜结合不会引发成孔MACPF（膜攻击复合物/穿孔素样）结构域发生不可逆的构象变化，这表明穿孔素形成孔道需要随后在膜表面发生单体-单体相互作用。
