2 A crystal structure of an extracellular fragment of human CD40 ligand.
BACKGROUND
The CD40 ligand (CD40L) is a member of the tumor necrosis factor (TNF) family of proteins and is transiently expressed on the surface of activated T cells. The binding of CD40L to CD40, which is expressed on the surface of B cells, provides a critical and unique pathway of cellular activation resulting in antibody isotype switching, regulation of apoptosis, and B cell proliferation and differentiation. Naturally occurring mutations of CD40L result in the clinical hyper-IgM syndrome, characterized by an inability to produce immunoglobulins of the IgG, IgA and IgE isotypes.


RESULTS
We have determined the crystal structure of a soluble extracellular fragment of human CD40L to 2 A resolution and with an R factor of 21.8%. Although the molecule forms a trimer similar to that found for other members of the TNF family, such as TNF alpha and lymphotoxin-alpha, and exhibits a similar overall fold, there are considerable differences in several loops including those predicted to be involved in CD40 binding.


CONCLUSIONS
The structure suggests that most of the hyper-IgM syndrome mutations affect the folding and stability of the molecule rather than the CD40-binding site directly. Despite the fact that the hyper-IgM syndrome mutations are dispersed in the primary sequence, a large fraction of them are clustered in space in the vicinity of a surface loop, close to the predicted CD40-binding site.
Karpusas
M
M
Biogen, Inc., Cambridge, MA 02142, USA.
Hsu
Y M
YM
Wang
J H
JH
Thompson
J
J
Lederman
S
S
Chess
L
L
Thomas
D
D
D000595:Amino Acid Sequence; D001665:Binding Sites; D023201:CD40 Ligand; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D007075:Immunoglobulin M / Q000172:deficiency / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry
D007075:Immunoglobulin M; D008233:Lymphotoxin-alpha; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand