Three-dimensional modeling of a pre-B-cell receptor.
Signals delivered by the immunoglobulin (Ig)-like pre-B-cell receptor (pre-BCR) are critical for efficient maturation of early precursor B (pre-B) cells. A pre-BCR contains two immunoglobulin mu-heavy chains (muHC), two surrogate light chains (SLC) consisting of the non-covalently associated polypeptides, VpreB and lambda5, and the heterodimeric signaling transducer Igalpha/beta. Although, it is generally accepted that signals initiated from the pre-BCR are required for efficient expansion and differentiation of pre-B cells, the three-dimensional structure of this receptor has not yet been determined by either NMR or X-ray spectroscopy. Therefore, we used indirect computer-assisted molecular modeling techniques to predict for the first time three-dimensional coordinates of the pre-BCR, the conformation of the SLC components, VpreB and lambda5, and the position and flexibility of the so-called non-Ig-like unique tails at the C-terminus of VpreB and the N-terminus of lambda5. Structure prediction revealed that these unique tails of VpreB and lambda5 protrude from the SLC at the position where the CDR3 of a conventional IgLchain would be located. Thus, the unique tails are accessible for ligand binding, which supports the recent finding that the lambda5 unique tail is required for pre-BCR/stroma cell interaction. Further, the non-covalent interaction of the extra beta-strand of lambda5 (beta8) with VpreB is predicted to result in a stabilization of the tertiary structure of VpreB. In summary, three-dimensional computer modeling suggests that the structure of a pre-BCR resembles that of a conventional B-cell receptor (BCR) and that the lambda5 unique tail could be a major binding site for pre-BCR ligands.
Lanig
Harald
H
Computer Chemistry Center, University of Erlangen-Nürnberg, Nägelsbachstrasse 25, D-91052 Erlangen, Germany. lanig@chemie.uni-erlangen.de
Bradl
Harald
H
Jäck
Hans-Martin
HM
D000595:Amino Acid Sequence; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054420:Pre-B Cell Receptors; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011947:Receptors, Antigen, B-Cell; D016415:Sequence Alignment; D013057:Spectrum Analysis; D013211:Staphylococcus aureus / Q000276:immunology
D007140:Immunoglobulin Fab Fragments; D008562:Membrane Glycoproteins; D054420:Pre-B Cell Receptors; D011947:Receptors, Antigen, B-Cell