pH-dependent interdomain tethers of CD1b regulate its antigen capture.
As CD1 proteins recycle between the cell surface and endosomes, they show altered receptiveness to lipid antigen loading. We hypothesized that changes in proton concentration encountered within distinct endosomal compartments influence the charge state of residues near the entrance to the CD1 groove and thereby control antigen loading. Molecular dynamic models identified flexible areas of the CD1b heavy chain in the superior and lateral walls of the A' pocket. In these same areas, residues that carry charge in a pH-dependent manner (D60, E62) were found to tether the rigid alpha1 helix to flexible areas of the alpha2 helix and the 50-60 loop. After disruption of these tethers with acid pH or mutation, we observed increased association and dissociation of lipids with CD1b and preferential presentation of antigens with bulky lipid tails. We propose that ionic tethers act as molecular switches that respond to pH fluxes during endosomal recycling and regulate the conformation of the CD1 heavy chain to control the size and rate of antigens captured.
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Smith Building Room 514, 1 Jimmy Fund Way, Boston, MA 02115, USA.
Miguel
M
Relloso
Tan-Yun
TY
Cheng
Jin S
JS
Im
Emilio
E
Parisini
Carme
C
Roura-Mir
Charles
C
DeBono
Dirk M
DM
Zajonc
Leonel F
LF
Murga
Mary Jo
MJ
Ondrechen
Ian A
IA
Wilson
Steven A
SA
Porcelli
D Branch
DB
Moody
D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology*; D018949:Antigens, CD1 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D011992:Endosomes / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000276:immunology*; D050505:Mutant Proteins / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
D000941:Antigens; D018949:Antigens, CD1; C419394:CD1b antigen; D008055:Lipids; D050505:Mutant Proteins