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Structural basis of BLyS receptor recognition

Abstract

B lymphocyte stimulator (BLyS), a member of the tumor necrosis factor (TNF) superfamily, is a cytokine that induces B-cell proliferation and immunoglobulin secretion. We have determined the three-dimensional structure of BLyS to 2.0 Å resolution and identified receptor recognition segments using limited proteolysis coupled with mass spectrometry. Similar to other structurally determined TNF-like ligands, the BLyS monomer is a β-sandwich and oligomerizes to form a homotrimer. The receptor-binding region in BLyS is a deeper, more pronounced groove than in other cytokines. The conserved elements on the 'floor' of this groove allow for cytokine recognition of several structurally related receptors, whereas variations on the 'walls' and outer rims of the groove confer receptor specificity.

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Acknowledgements

The authors thank M. Zhang for her contribution in purifying BLyS protein, T. Kwong for excellent work preparing mass spectrometry experiments, other Arnold lab members and the staff at the Cornell High Energy Synchrotron Source and BioCARS at the Advanced Photon Source for assistance, C. Rosen for valuable discussions and enthusiastic support of the collaboration and the Arnold lab gratefully acknowledges HGS for financial support.

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Competing interests

The Arnold laboratory received funds from HGS to support some of the studies reported here. D.A.O. and E.A. were paid consultants to Human Genome Sciences, Inc., during part of the period during which this work was done. Y.L., O.G. and R.G. are employees of Human Genome Sciences, Inc.

Correspondence to Eddy Arnold.

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Further reading

Figure 1: Structural alignment of TNF-like cytokines.
Figure 2: BLyS structure.
Figure 3: Molecular surfaces of known TNF-family members.
Figure 4: Putative BLyS–receptor interactions.