CD38 (CD38 molecule)

	Gene structure of CD38. Colored boxes represent the 8 exons; the total length, the starting and ending base pair of the gene are indicated.
Description	The genomic DNA of CD38 extends for 71172 base pairs with 8 exons, starting at 15779898 bp and ending at 15851069 bp. The CD38 gene is located at 4p15.32. The 5'-flanking promoter region of the gene contains a CpG island that is ~900 bp long and includes exon 1 and the 5'-end of the intron 1. This region contains a binding site for the transcription factor Sp1 and several potential binding for other factors such as interleukins, interferon and hormones. A critical region in the CD38 gene is the retinoic acid responsive element (RARE) responsible for the upregulation of CD38 expression induced by all-trans retinoic acid (Nata et al., 1997; Ferrero and Malavasi, 1999). The 5'-end of the intron 1 contains also a C→ G single nucleotide polymorphism (SNP), rs6449182, that leads to the presence or absence of a PvuII restriction site (see below). The SNP is located within a putative E-box, a region of binding of the E proteins with a consequent regulation of gene transcription. In the B cell compartment a relevant role is played by E2A, that controls the expression of several B lineage genes. E2A was demonstrated to bind to the E-box of the CD38 gene, regulating its expression, and the binding of the protein is influenced by the CD38 genotype, with the G allele resulting in a stronger binding of E2A (Saborit-Villarroya et al., 2011).
Transcription	The mRNA of CD38 (NM_001775.2) contains 1494 bp.

	CD38 protein structure. CD38 is a transmembrane molecule of 300 aa. The intracellular (IC), the transmembrane (TM) and the extracellular domains are indicated in the diagram. The different portions of the aminoacidic chain are shown as coded by the different exons.
Description	Human CD38 is made up of a single chain of 300 aa with a corresponding molecular weight of approximately 45 kDa. It is characterized by a short cytoplasmic tail (21 aa), a small transmembrane domain (23 aa) and a large extracellular domain (256 aa). CD38 is a glycoprotein comprising 2 to 4 N-linked oligosaccharide chains containing sialic acid residues. The overall structure of the CD38 molecule is stabilized by six pairs of disulphide bonds. Besides the monomeric membrane-bound form of CD38, a soluble form of CD38 of approximately 78 kDa (p78) (Mallone et al., 1998) and a high-molecular weight form of 190 kDa (p190) (Umar et al., 1996), have been described. The latter fits with a tetrameric conformation of the molecule, both displaying enzymatic activities. The carboxyl-terminal of the molecule harbors the catalytic site (CD38 is defined as an ecto-enzyme) and the binding site for CD31, the non-substrate CD38 ligand (Deaglio et al., 1998). The overall structure of the CD38 molecule, obtained by crystallographic analyses, is "L"-shaped and can be divided into two separate domains. The N-terminal domain, formed by a bundle of α helices (α1, α2, α3, α5, α6) and two short β strands (β1, β3), and the C-terminal domain, formed by four-stranded parallel β sheet (β2, β4, β5, and β6) surrounded by two long (α8 and α9) and two short α helices (α4 and α7). These two distinct domains are connected by a hinge region composed of three peptide chains. The enzyme's overall topology is similar to the related proteins CD157 and the Aplysia ADP-ribosyl cyclase, with the exception of important structural changes at the two termini. The extended positively charged N terminus has lateral associations with the other CD38 molecule in the crystallographic asymmetric unit. The analysis of the CD38 substrate binding models revealed three key residues that may be critical in controlling CD38 enzimatic functions. Indeed, the positions of residues Glu226, Trp125, and Trp189, which are essential for the enzyme's catalytic activity are highly conserved; Trp125 and Trp189 are suggested as the residues for recognizing and positioning the substrate by hydrophobic interactions, while Glu226 is the catalytic residue that takes part in the formation of the catalytic intermediate) (Munshi et al., 2000; Liu et al., 2005).
Expression	Human CD38 is surface expressed by various cells of both hematopoietic and non-hematopoietic lineages. In the T cell compartment, CD38 is expressed by a significant fraction of human thymocytes, mainly at the double-positive stage. In B cells, the expression is tightly regulated during cell ontogenesis, being present at high levels in bone marrow precursors and in terminally differentiated plasma cells. CD38 is expressed also in circulating monocytes, but not in resident macrophages, and in circulating and residential NK cells and granulocytes. CD38 is also present in many tissues other than haematopoietic cells, including normal prostatic epithelial cells, pancreatic islet cells and the brain, where it is detected in perikarya and dendrites of many neurons, such as the cerebellar Purkinje cells, in rat astrocytes and in perivascular autonomic nerve terminals. Other CD38+ cells include smooth and striated muscle cells, renal tubules, retinal gangliar cells and cornea (Malavasi et al., 2008).
Localisation	CD38 is a type II transmembrane protein expressed on plasma and nuclear membranes.
Function	CD38 is a multifunctional ecto-enzyme involved in signal transduction, cell adhesion and calcium signaling. The binding to the ligand CD31, initiates a signaling cascade that includes phosphorylation of sequential intracellular targets and increases cytoplasmic Ca2+ levels, mediating different biological events depending on the cells type (e.g., activation, proliferation, apoptosis, cytokines secretion and homing). As an enzyme, CD38 metabolizes NAD+/NADP+, generating cADPR, ADP-ribose and NAADP (Lee, 2006). These products bind different receptors and channels (IP3 receptors IP3R, Ryanodine receptor RyR and Transient receptor potential cation channel subfamily M member 2 TRPM2) and are involved in the regulation of intracellular Ca2+ and activation of critical signaling pathways connected to the control of cell metabolism, genomic stability, apoptosis, cell signaling, inflammatory response and stress tolerance (Guse, 2005).
Homology	The CD38 gene is conserved in human, chimpanzee, dog, mouse, rat and chicken. Human CD38 shares a 25-30% homology in amino acid sequence to the Aplysia ADP ribosyl cyclase and it is highly homologous to CD157 (BST-1), originated by gene duplication (Ferrero and Malavasi, 1997; Ferrero and Malavasi, 1999).

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