The design and characterization of receptor-selective APRIL variants.

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Serval ID
serval:BIB_E62D4389A838
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The design and characterization of receptor-selective APRIL variants.
Journal
Journal of Biological Chemistry
Author(s)
Kimberley F.C., van der Sloot A.M., Guadagnoli M., Cameron K., Schneider P., Marquart J.A., Versloot M., Serrano L., Medema J.P.
ISSN
1083-351X (Electronic)
ISSN-L
0021-9258
Publication state
Published
Issued date
2012
Volume
287
Number
44
Pages
37434-37446
Language
english
Abstract
A proliferation-inducing ligand (APRIL), a member of the TNF ligand superfamily with an important role in humoral immunity, is also implicated in several cancers as a prosurvival factor. APRIL binds two different TNF receptors, B cell maturation antigen (BCMA) and transmembrane activator and cylclophilin ligand interactor (TACI), and also interacts independently with heparan sulfate proteoglycans. Because APRIL shares binding of the TNF receptors with B cell activation factor, separating the precise signaling pathways activated by either ligand in a given context has proven quite difficult. In this study, we have used the protein design algorithm FoldX to successfully generate a BCMA-specific variant of APRIL, APRIL-R206E, and two TACI-selective variants, D132F and D132Y. These APRIL variants show selective activity toward their receptors in several in vitro assays. Moreover, we have used these ligands to show that BCMA and TACI have a distinct role in APRIL-induced B cell stimulation. We conclude that these ligands are useful tools for studying APRIL biology in the context of individual receptor activation.
Keywords
Amino Acid Motifs, Amino Acid Sequence, Amino Acid Substitution, Animals, B-Cell Maturation Antigen, B-Lymphocytes/metabolism, B-Lymphocytes/physiology, Cell Survival, Crystallography, X-Ray, HEK293 Cells, Humans, Hydrogen Bonding, Immunoglobulin A/biosynthesis, Mice, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutant Proteins/chemistry, Protein Binding, Protein Structure, Tertiary, Protein Transport, Transmembrane Activator and CAML Interactor Protein, Tumor Necrosis Factor Ligand Superfamily Member 13/chemistry, Tumor Necrosis Factor Ligand Superfamily Member 13/genetics
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Web of science
Create date
29/11/2012 18:06
Last modification date
18/01/2020 6:17
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