A novel activating anti-beta1 integrin monoclonal antibody binds to the cysteine-rich repeats in the beta1 chain.
The functional status of an integrin depends on the conformation of its extracellular domain, which is controlled by the cell expressing that receptor. The transmission of regulatory signals from within the cell is considered to be via propagated conformational changes from the receptor's cytoplasmic tails to the extracellular ligand binding "pocket." The end result is increased accessibility of the ligand binding pocket in the high affinity ("active") form of integrins. We report a novel monoclonal antibody (QE.2E5) that binds within the cysteine-rich repeats in the integrin beta1 chain and induces high affinity binding of fibronectin to the integrin alpha5beta1. The QE.2E5 epitope is located approximately 200 residues both from the predicted binding site for fibronectin and from the epitopes recognized by other activating anti-beta1 monoclonal antibodies. It is also expressed on beta1 integrins from a number of nonhuman species. Although they have the same functional effects, the binding of QE.2E5 and another activating antibody (8A2) to the receptor have contrasting effects on the expression of an activation-dependent epitope in the beta1 chain. We propose that the cysteine-rich repeats contain a regulatory region that is distinct from those previously described in the integrin beta1 chain.
Faull
R J
RJ
Renal Unit, Royal Adelaide Hospital, North Terrace, Adelaide 5000, South Australia, Australia.
Wang
J
J
Leavesley
D I
DI
Puzon
W
W
Russ
G R
GR
Vestweber
D
D
Takada
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D001665:Binding Sites; D001666:Binding Sites, Antibody; D002448:Cell Adhesion; D002460:Cell Line; D003545:Cysteine; D004730:Endothelium, Vascular / Q000276:immunology / Q000502:physiology*; D000939:Epitopes / Q000032:analysis / Q000737:chemistry; D005353:Fibronectins; D006801:Humans; D019012:Integrin beta1 / Q000032:analysis / Q000276:immunology* / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins
D000911:Antibodies, Monoclonal; D000939:Epitopes; D005353:Fibronectins; D019012:Integrin beta1; D008024:Ligands; D011993:Recombinant Fusion Proteins; D003545:Cysteine