title: The design and characterization of receptor-selective APRIL variants.
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.
authors.affiliation: Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, University of Amsterdam, Amsterdam 1105 A2, The Netherlands.
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Kimberley
authors.forename: Almer M
authors.initials: AM
authors.lastname: van der Sloot
authors.forename: Marco
authors.initials: M
authors.lastname: Guadagnoli
authors.forename: Katherine
authors.initials: K
authors.lastname: Cameron
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: J Arnoud
authors.initials: JA
authors.lastname: Marquart
authors.forename: Miranda
authors.initials: M
authors.lastname: Versloot
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D053301:B-Cell Maturation Antigen; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology; D002470:Cell Survival; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D007070:Immunoglobulin A / Q000096:biosynthesis; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000737:chemistry* / Q000235:genetics*
chemical_list: D053301:B-Cell Maturation Antigen; D007070:Immunoglobulin A; D050505:Mutant Proteins; C108467:TNFRSF13B protein, human; C086966:TNFRSF17 protein, human; C491959:Tnfsf13 protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13