Dataset Information

How natalizumab binds and antagonizes ?4 integrins.

ABSTRACT: Natalizumab antibody to ?4-integrins is used in therapy of multiple sclerosis and Crohn's disease. A crystal structure of the Fab bound to an ?4 integrin ?-propeller and thigh domain fragment shows that natalizumab recognizes human-mouse differences on the circumference of the ?-propeller domain. The epitope is adjacent to but outside of a ligand-binding groove formed at the interface with the ?-subunit ?I domain and shows no difference in structure when bound to Fab. Competition between Fab and the ligand vascular cell adhesion molecule (VCAM) for binding to cell surface ?4?1 shows noncompetitive antagonism. In agreement, VCAM docking models suggest that binding of domain 1 of VCAM to ?4-integrins is unimpeded by the Fab, and that bound Fab requires a change in orientation between domains 1 and 2 of VCAM for binding to ?4?1. Mapping of species-specific differences onto ?4?1 and ?4?7 shows that their ligand-binding sites are highly conserved. Skewing away from these conserved regions of the epitopes recognized by current therapeutic function-blocking antibodies has resulted in previously unanticipated mechanisms of action.

SUBMITTER: Yu Y

PROVIDER: S-EPMC3820868 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Publications

How natalizumab binds and antagonizes α4 integrins.

Yu Yamei Y Schürpf Thomas T Springer Timothy A TA

The Journal of biological chemistry 20130918 45

Natalizumab antibody to α4-integrins is used in therapy of multiple sclerosis and Crohn's disease. A crystal structure of the Fab bound to an α4 integrin β-propeller and thigh domain fragment shows that natalizumab recognizes human-mouse differences on the circumference of the β-propeller domain. The epitope is adjacent to but outside of a ligand-binding groove formed at the interface with the β-subunit βI domain and shows no difference in structure when bound to Fab. Competition between Fab and ...[more]

PMID: 24047894

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Project description:The virion of dengue virus (DENV) is composed of a viral envelope covering a nucleocapsid formed by a complex of viral genomic RNA and core protein (CP). DENV CP forms a dimer via the internal α2 and α4 helices of each monomer. Pairing of α2-α2' creates a continuous hydrophobic surface, while the α4-α4' helix pair joins the homodimer via side-chain interactions of the inner-edge residues. However, the importance of dimer conformation and the α4 helix of DENV CP in relation to its function are poorly understood. Loss of association between CP and lipid droplets (LDs) due to mutation suggests that the CP hydrophobic surface was not exposed, offering a possible explanation for the absence of dimers. Further assays suggest the connection between CP folding and protein stability. Attenuation of full-length RNA-derived virus production is associated with CP mutation, since no significant defects were detected in virus translation and replication. The in vitro characterization assays further highlighted that the α4-α4' helix pair conformation is critical in preserving the overall α-helical content, thermostability, and dimer formation ability of CP, features correlated with the efficiency of nucleocapsid formation. Addition of Tween 20 improves in vitro nucleocapsid-like particle formation, suggesting the role of the LD in nucleocapsid formation in vivo. This study provides the first direct link between the α4-α4' helix pair interaction and the CP dimer conformation that is the basis of CP function, particularly in nucleocapsid formation during virion production. Importance: Structure-based mutagenesis study of the dengue virus core protein (CP) reveals that the α4-α4' helix pair is the key to maintaining its dimer conformation, which is the basis of CP function in nucleocapsid formation and virus production. Attenuation of full-length RNA-derived virus production is associated with CP mutation, since no significant defects in virus translation and replication were detected. In vitro inefficiency and size of nucleocapsid-like particle (NLP) formation offer a possible explanation for in vivo virus production inefficiency upon CP mutation. Further, the transition of NLP morphology from an incomplete state to an intact particle shown by α4-α4' helix pair mutants in the presence of a nonionic detergent suggests the regulatory role of the intracellular lipid droplet (LD) in CP-LD interaction and in promoting nucleocapsid formation. This study provides the first direct link between the α4-α4' helix pair interaction and CP dimer conformation that is the fundamental requirement of CP function, particularly in nucleocapsid formation during virion production.

Dataset Information

How natalizumab binds and antagonizes ?4 integrins.

Publications

How natalizumab binds and antagonizes α4 integrins.

Similar Datasets

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