Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling. Essential for trafficking and compartmentalization of CD19 receptor on the surface of activated B cells. Upon initial encounter with microbial pathogens, enables the assembly of CD19-CR2/CD21 and B cell receptor (BCR) complexes at signaling TERMs, lowering the threshold dose of antigen required to trigger B cell clonal expansion and antibody production. In T cells, facilitates the localization of CD247/CD3 zeta at antigen-induced synapses with B cells, providing for costimulation and polarization toward T helper type 2 phenotype. Present in MHC class II compartments, may also play a role in antigen presentation (By similarity). Can act both as positive and negative regulator of homotypic or heterotypic cell-cell fusion processes. Positively regulates sperm-egg fusion and may be involved in acrosome reaction. In myoblasts, associates with CD9 and PTGFRN and inhibits myotube fusion during muscle regeneration (By similarity). In macrophages, associates with CD9 and beta-1 and beta-2 integrins, and prevents macrophage fusion into multinucleated giant cells specialized in ingesting complement-opsonized large particles (By similarity). Also prevents the fusion of mononuclear cell progenitors into osteoclasts in charge of bone resorption (By similarity). May regulate the compartmentalization of enzymatic activities. In T cells, defines the subcellular localization of dNTPase SAMHD1 and permits its degradation by the proteasome, thereby controlling intracellular dNTP levels (By similarity). Also involved in cell adhesion and motility. Positively regulates integrin-mediated adhesion of macrophages, particularly relevant for the inflammatory response in the lung (By similarity). Homodimer. Part of a complex composed of CD19, CR2/CD21, CD81 and IFITM1/CD225 in the membrane of mature B cells. Interacts (via the second extracellular domain) with CD19; this interaction is initiated early during biosynthesis in the ER and enables trafficking of only properly folded CD19. Part of a complex that includes MHC class II/HLA-DR molecules and IFITM1. Interacts with IFITM1 (By similarity). Interacts with IFITM2 and IFITM3 (By similarity). Part of integrin-tetraspanin complex composed of CD9, CD81, beta-1 and beta-2 integrins in the membrane of monocyte/macrophages. Interacts (via the second extracellular domain) with integrin ITGAV:ITGB3. Interacts with CD247/CD3 zeta, ICAM1 and CD9 at the immune synapse on T cell membrane (By similarity). Part of a GPCR-tetraspanin complex consisting at least of ADGRG1, CD81, possibly CD9, and GNA11 in which CD81 enhances the association of ADGRG1 with GNA11. Part of a complex composed of CD9, CD81, PTGFRN and IGSF8 (By similarity). Interacts directly with IGSF8. Interacts with CD53 and SCIMP. Interacts with SAMHD1 (via its C-terminus) (By similarity). Interacts with glypican GPC3 and with the transcriptional repressor HHEX; binding to GPC3 decreases the availability of free CD81 for binding to HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Interacts with CLDN1. Interacts with CLDN6 and CLDN9 (By similarity). Associates with CLDN1 and the CLDN1-CD81 complex localizes to the basolateral cell membrane. Binds cholesterol in a cavity lined by the transmembrane spans. Not glycosylated. Likely constitutively palmitoylated at low levels. Protein palmitoylation is up-regulated upon coligation of BCR and CD9-C2R-CD81 complexes in lipid rafts. Belongs to the tetraspanin (TM4SF) family.