Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes.
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.
Karpusas
Michael
M
Biogen, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. michael_karpusas@biogen.com
Cachero
Teresa G
TG
Qian
Fang
F
Boriack-Sjodin
Ann
A
Mullen
Colleen
C
Strauch
Kathy
K
Hsu
Yen-Ming
YM
Kalled
Susan L
SL
D000595:Amino Acid Sequence; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000187:drug effects*; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D006801:Humans; D006860:Hydrogen Bonding; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D012997:Solvents / Q000378:metabolism; D055672:Static Electricity; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
C490341:ANP32B protein, human; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D008565:Membrane Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; D012997:Solvents; C435926:TNFRSF13C protein, human; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha