2 A crystal structure of an extracellular fragment of human CD40 ligand

Structure. 1995 Oct 15;3(10):1031-9. doi: 10.1016/s0969-2126(01)00239-8.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • CD40 Ligand
  • Crystallography, X-Ray / methods
  • Humans
  • Immunoglobulin M / deficiency
  • Immunoglobulin M / genetics
  • Immunologic Deficiency Syndromes / genetics
  • Lymphotoxin-alpha / chemistry
  • Membrane Glycoproteins / chemistry*
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Conformation
  • Sequence Homology, Amino Acid
  • Tumor Necrosis Factor-alpha / chemistry


  • Immunoglobulin M
  • Lymphotoxin-alpha
  • Membrane Glycoproteins
  • Tumor Necrosis Factor-alpha
  • CD40 Ligand