Chattopadhyay Kausik, Ramagopal Udupi A, Brenowitz Michael, Nathenson Stanley G, Almo Steven C
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):635-40. doi: 10.1073/pnas.0710529105. Epub 2008 Jan 8.
Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. In contrast to all previously characterized homotrimeric TNF family members, the mouse GITRL crystal structure reveals a previously unrecognized dimeric assembly that is stabilized via a unique "domain-swapping" interaction. Consistent with its crystal structure, mouse GITRL exists as a stable dimer in solution. Structure-guided mutagenesis studies confirmed the determinants responsible for dimerization and support a previously unrecognized receptor-recognition surface for mouse GITRL that has not been observed for any other TNF family members. Taken together, the unique structural and biochemical behavior of mouse GITRL, along with the unusual domain organization of murine GITR, support a previously unrecognized mechanism for signaling within the TNF superfamily.
糖皮质激素诱导的TNF受体配体(GITRL)是TNF超家族中最近发现的成员,它在效应T细胞和调节性T细胞上与其受体GITR结合,并产生涉及多种T细胞功能的正向共刺激信号。与所有先前表征的同源三聚体TNF家族成员不同,小鼠GITRL晶体结构揭示了一种以前未被识别的二聚体组装,该组装通过独特的“结构域交换”相互作用得以稳定。与其晶体结构一致,小鼠GITRL在溶液中以稳定的二聚体形式存在。结构导向的诱变研究证实了负责二聚化的决定因素,并支持了小鼠GITRL以前未被识别的受体识别表面,这在任何其他TNF家族成员中都未观察到。综上所述,小鼠GITRL独特的结构和生化行为,以及小鼠GITR不寻常的结构域组织,支持了TNF超家族中一种以前未被识别的信号传导机制。