CD38 - CD38 molecule |Elisa - Clia - Antibody - Protein

Background

CD38 is a multifunctional membrane glycoprotein expressed on a variety of cells, including immune cells (B cells, T cells, monocytes, and natural killer cells), as well as non-hematopoietic cells like those in the pancreas, brain, and muscle. Initially identified as a cell-surface receptor on lymphocytes, CD38 has since been recognized for its roles in enzyme-mediated metabolism, cell adhesion, and signal transduction. This protein is particularly well-known for its enzymatic activity in catalyzing the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) from NAD+, which serves as an important second messenger in calcium signaling pathways. CD38 plays crucial roles in the regulation of intracellular calcium levels, influencing processes such as cell activation, proliferation, and differentiation.

Due to its widespread expression and enzymatic activities, CD38 has been implicated in various physiological and pathological processes, including immune responses, cancer progression, and metabolic disorders. The molecule is a target for therapeutic interventions, particularly in B-cell malignancies such as multiple myeloma and chronic lymphocytic leukemia (CLL), where it is overexpressed and contributes to the survival and proliferation of malignant cells.

Protein Structure

The CD38 molecule is a type II transmembrane glycoprotein with a single transmembrane domain, which distinguishes it from other cell-surface receptors that possess multiple transmembrane segments. The structural components of CD38 include:

N-terminal Intracellular Domain:

• The N-terminal region of CD38 is a small intracellular tail of about 20 amino acids. This region is involved in signaling pathways and serves as a point of interaction with intracellular signaling proteins.

Single Transmembrane Domain:

• CD38 has one hydrophobic transmembrane helix, which anchors the molecule in the cell membrane. This domain is crucial for the orientation of CD38 and its association with other membrane proteins.

Extracellular Domain:

The bulk of CD38’s structure lies in its extracellular domain, which is responsible for both its enzymatic activity and ligand-binding capabilities. The extracellular domain contains binding sites for NAD+ and related substrates. CD38 is unique in that it catalyzes several reactions, including:

• The cyclization of NAD+ to form cyclic ADP-ribose (cADPR).
• The hydrolysis of cADPR to form ADP-ribose.
• The synthesis of nicotinic acid adenine dinucleotide phosphate (NAADP), another key molecule involved in calcium signaling.

The active site of CD38 lies in this extracellular domain and has been studied extensively for its catalytic functions. This region is glycosylated at several residues, a modification that stabilizes the protein and is important for its recognition by other proteins in cellular signaling processes.

Dimerization of CD38 is also a significant structural feature, as the protein can exist as a monomer or homodimer, which may influence its enzymatic activity and interactions with other proteins.

The overall structure of CD38 resembles that of other ADP-ribosyl cyclases, a family of enzymes involved in NAD+ metabolism. The crystal structure of CD38 reveals that its extracellular domain contains a Rossmann fold typical of nucleotide-binding enzymes, further confirming its role in NAD+ metabolism.

Classification and Subtypes

CD38 belongs to the ADP-ribosyl cyclase family of enzymes. It shares homology with other members of this family, such as CD157 (BST-1), which also participates in NAD+ metabolism. While CD38 itself does not have distinct subtypes, its function and expression can be modulated by various isoforms or splice variants in different tissues, which may alter its enzymatic properties or cell-surface distribution.

CD38’s expression varies depending on the cell type and state of differentiation, particularly in the immune system, where it is highly expressed on activated B and T cells, plasma cells, and macrophages. This variation in expression contributes to the differential roles CD38 plays across various tissues and cell types.

Function and Biological Significance

CD38 is a multifunctional protein with roles in enzymatic catalysis, signal transduction, and cell adhesion. Its primary functions are outlined below:

Enzymatic Functions:

• CD38’s most significant role is in NAD+ metabolism, where it acts as an ADP-ribosyl cyclase. It catalyzes the production of cyclic ADP-ribose (cADPR), a potent second messenger that regulates intracellular calcium release from stores such as the endoplasmic reticulum. Calcium is a key signaling ion in many cellular processes, including muscle contraction, immune cell activation, and neurotransmitter release.
• CD38 can also synthesize nicotinic acid adenine dinucleotide phosphate (NAADP), another important calcium-signaling molecule. NAADP is involved in releasing calcium from acidic organelles such as lysosomes, which expands the range of CD38’s regulatory functions.
• The hydrolysis of NAD+ by CD38 produces ADP-ribose, which is involved in various signaling pathways, including those related to energy metabolism and immune responses.

Cell Adhesion:

• CD38 can mediate cell-cell interactions through its role as a receptor. For example, it interacts with CD31 (PECAM-1), facilitating immune cell adhesion, which is important in processes like inflammation, tissue repair, and immune surveillance.

Signal Transduction:

• In the immune system, CD38 acts as a signaling receptor. Upon ligation, it triggers signaling cascades that affect immune cell activation, differentiation, and proliferation. CD38’s expression is dynamically regulated during immune responses, particularly in T cells, B cells, and plasma cells.
• In B cells, CD38 is essential for plasma cell differentiation and antibody production, making it a key player in humoral immunity.

Role in Energy Metabolism:

• CD38’s involvement in NAD+ degradation has implications for energy metabolism and aging. NAD+ is a central metabolite in cellular energy homeostasis, and CD38’s enzymatic activity reduces intracellular NAD+ levels, potentially influencing metabolic and aging-related processes.

Calcium Signaling:

• CD38’s role in calcium signaling extends beyond immune cells, influencing a variety of physiological systems, including insulin secretion in pancreatic β-cells and the regulation of neural functions in the brain.

Clinical Issues

CD38 is involved in several pathological conditions, particularly in immune-related diseases and cancers. The following are key clinical implications of CD38:

Cancer:

• Multiple Myeloma: CD38 is highly expressed on multiple myeloma cells, a type of plasma cell cancer. It serves as a target for monoclonal antibody therapies, such as daratumumab, which induce tumor cell death through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
• Chronic Lymphocytic Leukemia (CLL): CD38 expression is also elevated in CLL, where it is associated with poor prognosis and aggressive disease progression. CD38 is a marker of activation in CLL cells and serves as a therapeutic target.

Immunological Disorders:

• CD38 plays a role in autoimmune diseases, given its regulation of immune responses. For example, CD38 may influence the development of systemic lupus erythematosus (SLE), where abnormal immune activation leads to tissue damage.
• HIV: CD38 expression is increased in HIV infection, particularly on activated T cells. Elevated CD38 expression on T cells is associated with immune activation and has been used as a prognostic marker for disease progression.

Metabolic Disorders:

• CD38 has been linked to insulin secretion in pancreatic β-cells, suggesting that its dysregulation may contribute to diabetes. By modulating NAD+ levels and calcium signaling, CD38 may influence insulin release and glucose metabolism.

Aging and Neurodegeneration:

• CD38’s regulation of NAD+ levels is associated with aging processes. As CD38 degrades NAD+, reduced NAD+ availability has been linked to age-related metabolic decline and neurodegenerative diseases. Inhibiting CD38 has been proposed as a potential therapeutic strategy to boost NAD+ levels and ameliorate aging-related conditions.

Summary

CD38 is a versatile molecule with critical functions in NAD+ metabolism, immune regulation, calcium signaling, and cell adhesion. Its structure as a type II transmembrane protein with enzymatic and receptor functions enables it to regulate intracellular calcium levels and energy metabolism. CD38 is highly relevant in immune cell activation and differentiation, especially in B and T cells, where it contributes to immune responses and antibody production.

Clinically, CD38 is a target in the treatment of cancers such as multiple myeloma and CLL, where its overexpression promotes tumor cell survival. Additionally, CD38 is implicated in metabolic disorders, neurodegeneration, and autoimmune diseases. Ongoing research into CD38’s structure and function holds promise for developing novel therapeutic strategies, particularly in the fields of oncology, immunology, and aging-related diseases.