Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex.
Five CD28-like proteins exert positive or negative effects on immune cells. Only four of these five receptors interact with members of the B7 family. The exception is BTLA (B and T lymphocyte attenuator), which instead interacts with the tumor necrosis factor receptor superfamily member HVEM (herpes virus entry mediator). To better understand this interaction, we determined the 2.8-A crystal structure of the BTLA-HVEM complex. This structure shows that BTLA binds the N-terminal cysteine-rich domain of HVEM and employs a unique binding surface compared with other CD28-like receptors. Moreover, the structure shows that BTLA recognizes the same surface on HVEM as gD (herpes virus glycoprotein D) and utilizes a similar binding motif. Light scattering analysis demonstrates that the extracellular domain of BTLA is monomeric and that BTLA and HVEM form a 1:1 complex. Alanine-scanning mutagenesis of HVEM was used to further define critical binding residues. Finally, BTLA adopts an immunoglobulin I-set fold. Despite structural similarities to other CD28-like members, BTLA represents a unique co-receptor.
Compaan
Deanne M
DM
Department of Protein Engineering, Genentech, Inc., S. San Francisco, California 94080, USA.
Gonzalez
Lino C
LC
Tom
Irene
I
Loyet
Kelly M
KM
Eaton
Dan
D
Hymowitz
Sarah G
SG
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D008027:Light; D008214:Lymphocytes / Q000276:immunology; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry; D016254:Mutagenesis, Insertional; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012542:Scattering, Radiation; D017386:Sequence Homology, Amino Acid; D014759:Viral Envelope Proteins / Q000737:chemistry
C482586:BTLA protein, human; D046912:Multiprotein Complexes; D011971:Receptors, Immunologic; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; D011994:Recombinant Proteins; C506028:TNFRSF14 protein, human; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1