Structural basis of BLyS receptor recognition

Oren, Deena A.; Li, Yuling; Volovik, Yulia; Morris, Tina S.; Dharia, Chhaya; Das, Kalyan; Galperina, Olga; Gentz, Reiner; Arnold, Edward

doi:10.1038/nsb769

Cited by 80 publications

(53 citation statements)

References 40 publications

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“…However, calcium binding is an inherent property for C1q family proteins. TNF family proteins usually contain no metals, with few exceptions (25). According to our results, the conserved polar residue corresponding to Glu 1084 of hCap2_CRD is responsible, at least partially, for the intrinsic calcium binding nature of C1q family proteins.…”

Section: Discussionmentioning

confidence: 85%

“…B-D, DAEA mutant, wild-type Cap2_CRD and the latter treated with EDTA were eluted from gel filtration column as trimer, a mixture of trimer and monomer, and monomer, respectively. However, their apparent molecular masses (25,14, and 9 kDa) calculated from gel filtration standard are obviously lower than expected for unknown reasons. E and F, dynamic light scattering analysis showed that wild-type hCap2_CRD and hCap2_DAEA both exhibit a single peak, and they have a similar average hydrodynamic radius with an estimated molecular mass (MW) of 60 kDa.…”

Section: Discussionmentioning

confidence: 99%

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Structural Insights into the C1q Domain of Caprin-2 in Canonical Wnt Signaling

Miao

Jia

Xie

et al. 2014

Journal of Biological Chemistry

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Background: Caprin-2 is a newly identified regulator in canonical Wnt signaling. Results: Mutants targeting trimer contacts of Caprin-2 CRD rather than calcium-binding sites affect the function of Caprin-2 in canonical Wnt signaling. Conclusion: Caprin-2 CRD forms a flexible homotrimer mediated by calcium, and this trimeric assembly is required for the function of Caprin-2. Significance: This work facilitates our understanding of how Caprin-2 functions in canonical Wnt signaling.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Structural Insights into the C1q Domain of Caprin-2 in Canonical Wnt Signaling

Miao

Jia

Xie

et al. 2014

Journal of Biological Chemistry

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“…Like most members of the TNF family, the extracellular domain of TALL-1 can be cleaved to form a soluble cytokine (2). Crystal structure studies suggest that soluble TALL-1 (sTALL-1) 3 contains an unique "flap" region that is important for its virus-like assembly, receptor binding, and biological activities (7)(8)(9).…”

Section: Tnfr-associatedmentioning

confidence: 99%

TNFR-Associated Factor-3 Is Associated With BAFF-R and Negatively Regulates BAFF-R-Mediated NF-κB Activation and IL-10 Production

Shu

2002

The Journal of Immunology

138

126

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TALL-1 is a member of the TNF family that is critically involved in B cell survival, maturation, and progression of lupus-like autoimmune diseases. TALL-1 has three receptors, including BCMA, TACI, and BAFF-R, which are mostly expressed by B lymphocytes. Gene knockout studies have indicated that BAFF-R is the major stimulatory receptor for TALL-1 signaling and is required for normal B cell development. The intracellular signaling mechanisms of BAFF-R are not known. In this report, we attempted to identify BAFF-R-associated downstream proteins by yeast two-hybrid screening. This effort identified TNFR-associated factor (TRAF)3 as a protein specifically interacting with BAFF-R in yeast two-hybrid assays. Coimmunoprecipitation experiments indicated that BAFF-R interacts with TRAF3 in B lymphoma cells and this interaction is stimulated by TALL-1 treatment. Domain mapping experiments indicated that both a 6-aa membrane proximal region and the C-terminal 35 aa of BAFF-R are required for its interaction with TRAF3. Moreover, overexpression of TRAF3 inhibits BAFF-R-mediated NF-κB activation and IL-10 production. Taken together, our findings suggest that TRAF3 is a negative regulator of BAFF-R-mediated NF-κB activation and IL-10 production.

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“…The design of the fusion toxin was assisted by structural studies (39) suggesting that the trimeric nature and the COOH terminus of the natural BLyS molecule may be of critical importance to receptor recognition. We therefore designed this fusion toxin with the rGel component fused to the NH 2 terminus of the BLyS molecule.…”

Section: Construction Expression and Purification Of Rgel/ Blys Fusmentioning

confidence: 99%

The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

Lyu

Cheung

Hittelman

et al. 2007

Molecular Cancer Therapeutics

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B lymphocyte stimulator (BLyS) is crucial for B-cell survival, and the biological effects of BLyS are mediated by three cell surface receptors designated B cellactivating factor receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antibody (BCMA). Increased expression of BLyS and its receptors has been identified in numerous B-cell malignancies. We generated a fusion toxin designated rGel/BLyS for receptor-mediated delivery of the recombinant gelonin (rGel) toxin to neoplastic B cells, and we characterized its activity against various B-cell tumor lines. Three mantle cell lymphoma (MCL) cell lines (JeKo-1, Mino, and SP53) and two diffuse large B-cell lymphoma (DLBCL) cell lines (SUDHL-6 and OCI-Ly3) expressing all three distinct BLyS receptors were found to be the most sensitive to the fusion toxin (IC 50 = 2 -5 pmol/L and 0.001 -5 nmol/L for MCL and DLBCL, respectively). The rGel/BLyS fusion toxin showed specific binding to cells expressing BLyS receptors and rapid internalization of the rGel component into target cells. The cytotoxic effects of rGel/BLyS were inhibited by pretreatment with free BLyS or with soluble BAFF-R, TACI, and BCMA decoy receptors. This suggests that the cytotoxic effects of the fusion toxin are mediated through BLyS receptors. The rGel/BLyS fusion toxin inhibited MCL cell growth through induction of apoptosis associated with caspase-3 activation and poly (ADP-ribose) polymerase cleavage. Our results suggest that BLyS has the potential to serve as an excellent targeting ligand for the specific delivery of cytotoxic molecules to neoplastic B cells expressing the BLyS receptors, and that the rGel/ BLyS fusion toxin may be an excellent candidate for the treatment of B-cell malignancies especially MCL and DLBCL. [Mol Cancer Ther 2007;6(2):460 -70]

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Structural basis of BLyS receptor recognition

Cited by 80 publications

References 40 publications

Structural Insights into the C1q Domain of Caprin-2 in Canonical Wnt Signaling

Structural Insights into the C1q Domain of Caprin-2 in Canonical Wnt Signaling

TNFR-Associated Factor-3 Is Associated With BAFF-R and Negatively Regulates BAFF-R-Mediated NF-κB Activation and IL-10 Production

The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

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