The design and characterization of receptor-selective APRIL variants.

TitleThe design and characterization of receptor-selective APRIL variants.
Publication TypeJournal Article
Year of Publication2012
AuthorsKimberley FC, van der Sloot AM, Guadagnoli M, Cameron K, Schneider P, Marquart AJ, Versloot M, Serrano L, Medema J P
JournalJ Biol Chem
Date Published2012 Oct 26
KeywordsAmino Acid Motifs, Amino Acid Sequence, Amino Acid Substitution, Animals, B-Cell Maturation Antigen, B-Lymphocytes, Cell Survival, Crystallography, X-Ray, HEK293 Cells, Humans, Hydrogen Bonding, Immunoglobulin A, Mice, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutant Proteins, Protein Binding, Protein Structure, Tertiary, Protein Transport, Transmembrane Activator and CAML Interactor Protein, Tumor Necrosis Factor Ligand Superfamily Member 13

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.

Alternate JournalJ. Biol. Chem.
PubMed ID22961987