Structural basis for the interaction between focal adhesion kinase and CD4.
Focal adhesion kinase (FAK) and CD4 fulfil vital functions in cellular signal transduction: FAK is a central component in integrin signalling, whereas CD4 plays essential roles in the immune defence. In T lymphocytes, FAK and CD4 localise to the same signalling complexes after stimulation by either the human immunodeficiency virus (HIV) gp120 glycoprotein or an antigen, suggesting the concerted action of FAK and CD4 in these cells. Using crystallography and microcalorimetry, we here show that the focal adhesion targeting (FAT) domain of FAK binds specifically to the CD4 endocytosis motif in vitro. This FAT-CD4 complex is structurally and thermodynamically similar to the one FAT forms with paxillin LD motifs. The CD4 binding site on FAT presents the same features as the established CD4 binding site on the HIV-1 Nef protein. The binding of FAT to CD4 is incompatible with the binding of Lck to CD4. We further show that HIV-1 gp120 triggers the association of CD4 with FAK in T cells, under conditions that are known to dissociate Lck from CD4. Our results suggest that the FAK-CD4 complex represents an alternative route for eliciting T-cell-specific signals and that it links gp120 engagement to distinctive T-cell signalling during HIV infection. In infected cells, HIV-1 Nef may displace FAK from CD4 to protect the cells from apoptosis.
Garron
Marie-Line
ML
INSERM, UMR554, 34090 Montpellier, France.
Arthos
James
J
Guichou
Jean-François
JF
McNally
Jonathan
J
Cicala
Claudia
C
Arold
Stefan T
ST
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001665:Binding Sites; D015704:CD4 Antigens / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002151:Calorimetry; D002460:Cell Line; D016384:Consensus Sequence; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D016018:Least-Squares Analysis; D018613:Microscopy, Confocal; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D051419:Paxillin / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019713:Receptors, CCR5 / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013816:Thermodynamics; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D051419:Paxillin; D010446:Peptide Fragments; D019713:Receptors, CCR5; D011994:Recombinant Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; D051416:Focal Adhesion Protein-Tyrosine Kinases