Karpusas Michael, Cachero Teresa G, Qian Fang, Boriack-Sjodin Ann, Mullen Colleen, Strauch Kathy, Hsu Yen-Ming, Kalled Susan L
Biogen, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
J Mol Biol. 2002 Feb 1;315(5):1145-54. doi: 10.1006/jmbi.2001.5296.
B cell activating factor (BAFF), a ligand belonging to the tumor necrosis factor (TNF) family, plays a critical role in regulating survival and activation of peripheral B cell populations and has been associated with autoimmune disease. BAFF is known to interact with three receptors, BCMA, TACI and BAFF-R, that have distant similarities with other receptors of the TNF family. We have determined the crystal structure of the TNF-homologous domain of BAFF at 2.8 A resolution. The structure reveals significant differences when compared to other TNF family members, including an unusually long D-E loop that participates in the formation of a deep, concave and negatively charged region in the putative receptor binding site. The BAFF structure was further used to generate a homology model of APRIL, a closely related TNF family ligand that also binds to BCMA and TACI, but not BAFF-R. Analysis of the putative receptor binding sites of BAFF and APRIL suggests that differences in the D-E loop structure and electrostatic surface potentials may be important for determining binding specificities for BCMA, TACI and BAFF-R.
B细胞活化因子（BAFF）是一种属于肿瘤坏死因子（TNF）家族的配体，在调节外周B细胞群体的存活和活化中起关键作用，并且与自身免疫性疾病相关。已知BAFF可与三种受体相互作用，即BCMA、TACI和BAFF-R，它们与TNF家族的其他受体有远缘相似性。我们已经确定了BAFF的TNF同源结构域在2.8埃分辨率下晶体结构。与其他TNF家族成员相比，该结构显示出显著差异，包括一个异常长的D-E环，它参与了在假定的受体结合位点形成一个深的、凹的和带负电荷的区域。BAFF结构还被进一步用于生成APRIL的同源模型，APRIL是一种密切相关的TNF家族配体，它也与BCMA和TACI结合，但不与BAFF-R结合。对BAFF和APRIL假定的受体结合位点的分析表明，D-E环结构和静电表面电位的差异对于确定与BCMA、TACI和BAFF-R的结合特异性可能很重要。
