Classification of mutations in the human CD40 ligand, gp39, that are associated with X-linked hyper IgM syndrome.
The interaction between the T cell activation antigen gp39 and CD40, its receptor CD40 on B cells, plays a critical role in the regulation of humoral immune responses. Using a detailed three-dimensional model of the gp39 extracellular region, we have analyzed 20 mutations in gp39 that were, with one exception, isolated from patients with X-linked hyper IgM (XHIM) syndrome. On the basis of this analysis, the mutations were classified according to their predicted locations and effects. Twelve mutations are thought to compromise the gp39 structure by affecting interactions in hydrophobic core regions or at monomer interfaces, whereas seven others map closely to gp39 residues important for interaction with CD40. The latter mutations may thus, directly or indirectly, interfere with CD40 binding. One naturally occurring mutant whose carrier displays normal immune responses maps to a solvent-exposed position in a loop region of the molecule.
Bajorath
J
J
Bristol-Meyers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA. bajorath@protos.bms.com
Seyama
K
K
Nonoyama
S
S
Ochs
H D
HD
Aruffo
A
A
D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics*; D007075:Immunoglobulin M; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D017354:Point Mutation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014960:X Chromosome
D019013:CD40 Antigens; D007075:Immunoglobulin M; D023201:CD40 Ligand