CRD1 mediates self-assembly of CD40 and is also required for CD40 expression ). The ICD of CD40 has several motifs that mediate interactions with downstream effectors of several signaling pathways.

), wherein 2 variant homozygotes departed phenotypically from 8 homozygous reference mice and 6 heterozygous mice (Figure 2). The mutation results in an cysteine (C) to arginine (R) substitution at position 23 (C23R) in all of the isoforms of the CD40 protein, and is strongly predicted by Poly Phen-2 to be benign (score = 0.013) ).

The mutation corresponds to residue 139 in the m RNA sequences NM_011611 (variant 1; within exon 2 of 9 total exons), NM_170703 (variant 2; within exon 2 of 8 total exons), NM_170704 (variant 4; within exon 2 of 9 total exons), and NM_170702 (variant 5; within exon 2 of 8 total exons). Similar to other members of the TNFR family, CD40 is a single-pass transmembrane-spanning protein with an extracellular domain (ECD; amino acids 24-193; SMART), a transmembrane domain (TMD; amino acids 193-215), and an intracellular domain (ICD; amino acids 216-289) [Figure 3; .

Ubiquitination can be inhibited by deubiquitinating enzymes (DUB).

Stimulation of the T-cell receptor (TCR) and B-cell receptor (BCR) results in the recruitment of Src and Syk family kinases. (1994) Gp39-CD40 Interactions are Essential for Germinal Center Formation and the Development of B Cell Memory.

Phosphorylation of p100 on two C-terminal sites triggers its polyubiquitination and proteasomal degradation to p52. D., Diakos, C., Kelemen, P., Kriehuber, E., Zeyda, M., Bohmig, G. (1989) The Human B Lymphocyte and Carcinoma Antigen, CDw40, is a Phosphoprotein Involved in Growth Signal Transduction.

Since p52 is typically associated with Rel B, activation of the non-canonical NF-κB pathway results in nuclear translocation of p52-Rel B dimers ]. (2002) The Lymphotoxin-Beta Receptor Induces Different Patterns of Gene Expression Via Two NF-kappa B Pathways.

Canonical and non-canonical NF-k B signaling pathways.

In the canonical pathway, several membrane receptors, including TNFR (tumor-necrosis factor receptor), IL-1R (interleukin-1 receptor) and TLRs (toll-like receptors), signal through kinases and adaptors (TRAFs), resulting in IKK activation.

A subset of TNFRs such as the lymphotoxin-β receptor (LT-βR), CD40, B-cell-activating factor receptor (BAFFR) and receptor activator of Nf-κB (RANK) can activate the canonical or non-canonical NF-κB signaling pathways. (1994) The Immune Responses in CD40-Deficient Mice: Impaired Immunoglobulin Class Switching and Germinal Center Formation.