CD37 - CD37 molecule |Elisa - Clia - Antibody - Protein

Background

CD37 is a member of the tetraspanin family, a group of membrane proteins involved in cellular signaling, adhesion, migration, and immune responses. It is primarily expressed on leukocytes, especially on B cells, T cells, monocytes, and dendritic cells. CD37 plays a pivotal role in organizing membrane microdomains called tetraspanin-enriched microdomains (TEMs), which serve as platforms for cell signaling, facilitating the clustering of various membrane proteins, including integrins and other receptors involved in immune regulation.

Unlike many other surface molecules, tetraspanins such as CD37 do not have a direct catalytic function but modulate the function of other molecules by influencing their spatial distribution and assembly in the membrane. This modulation affects immune cell functions, such as antigen presentation, cell adhesion, and migration, as well as B cell maturation and antibody production.

CD37's biological relevance has been underscored by its involvement in immune disorders, cancers, and its potential as a therapeutic target in B cell malignancies such as non-Hodgkin lymphoma. Research on CD37 has provided insight into its structural properties, biological functions, and its role in human diseases, particularly its regulatory effects on immune cells.

Protein Structure

The CD37 molecule is a tetraspanin, which means it has a structure that spans the plasma membrane four times, forming four distinct transmembrane domains. These four transmembrane segments are connected by two extracellular loops (one small, one large), and there are short cytoplasmic tails at both the N-terminal and C-terminal ends. The structural components of CD37 are detailed below:

Transmembrane Domains:

• CD37 consists of four hydrophobic transmembrane domains that anchor the protein within the lipid bilayer of the cell membrane. These regions are crucial for CD37’s ability to interact with other tetraspanins and membrane proteins, facilitating the formation of tetraspanin-enriched microdomains (TEMs).
• The transmembrane domains form interactions that allow CD37 to regulate the spatial organization of proteins in the membrane and engage in signaling processes.

Extracellular Loops:

• CD37 has two extracellular loops: the small extracellular loop (SEL) and the large extracellular loop (LEL). The large extracellular loop is important for interactions with other proteins and contains key sites for post-translational modifications like glycosylation.
• These extracellular loops are critical for CD37’s role in the immune response, enabling interactions with other cell surface molecules and influencing immune cell communication and activation.

Intracellular Domains:

• The short cytoplasmic tails at the N-terminal and C-terminal ends of CD37 play important roles in intracellular signaling and trafficking. These tails can interact with signaling molecules and other intracellular proteins, which helps mediate downstream cellular responses.
• Palmitoylation of CD37, a post-translational modification, occurs at specific cysteine residues in the cytoplasmic tails and is crucial for CD37's localization to tetraspanin-enriched microdomains.

The structure of CD37 is characteristic of the tetraspanin family and allows it to regulate various immune functions through its ability to influence the organization of other membrane proteins. It acts primarily as a scaffold protein, organizing signaling complexes on the cell surface.

Classification and Subtypes

CD37 belongs to the tetraspanin family of proteins, which are defined by their four transmembrane domains and ability to regulate other membrane proteins. Tetraspanins are found in many species and have homologs in humans, mice, and other organisms.

Within the tetraspanin family, CD37 is most closely related to other leukocyte-associated tetraspanins like CD9, CD53, and CD81, which share structural similarities and functional roles in immune cell signaling and organization.

CD37 itself does not have specific subtypes, but it forms hetero-oligomeric complexes with other tetraspanins and membrane proteins, influencing various immune functions. It can associate with proteins such as CD19 and CD20 on B cells, thereby regulating B cell responses.

Function and Biological Significance

CD37 plays crucial roles in immune cell function, particularly in B cells, T cells, and antigen-presenting cells. Key functions of CD37 include:

Regulation of B Cell Function:

• CD37 is highly expressed on mature B cells and plays a critical role in B cell responses. It regulates B cell receptor (BCR) signaling, modulating the activation and differentiation of B cells.
• By organizing signaling complexes on the B cell surface, CD37 influences antibody production and is involved in the maturation of B cells into plasma cells, which are responsible for producing immunoglobulins.

Modulation of Immune Responses:

• In dendritic cells and monocytes, CD37 is involved in the presentation of antigens to T cells. It helps regulate the strength and duration of immune responses by affecting the formation of immune synapses, where antigen-presenting cells communicate with T cells.
• CD37 also influences T cell activation, and its absence can lead to enhanced T cell proliferation and altered immune regulation, highlighting its importance in maintaining immune homeostasis.

Involvement in Apoptosis and Immune Regulation:

• CD37 has been implicated in the regulation of cell survival and apoptosis in immune cells. For example, CD37-deficient B cells show increased susceptibility to apoptosis, suggesting a role in promoting cell survival under certain conditions.
• In macrophages, CD37 modulates the inflammatory response by influencing the release of cytokines and other immune mediators.

Organization of Membrane Microdomains:

• As a member of the tetraspanin family, CD37 participates in the formation of tetraspanin-enriched microdomains (TEMs). These microdomains function as platforms that organize various signaling proteins on the cell membrane, influencing how cells respond to external signals.
• CD37 helps cluster important molecules such as MHC class II, CD19, and CD20 in B cells, regulating immune signaling and communication.

Host Defense and Immune Surveillance:

• CD37 contributes to the immune system’s ability to defend against infections. It is involved in immune surveillance by facilitating interactions between different immune cells, ensuring efficient immune responses against pathogens.

Clinical Issues

CD37 dysregulation or altered expression has been associated with several diseases, especially B cell malignancies, autoimmune diseases, and altered immune responses. Understanding the clinical implications of CD37 provides insights into its role in pathology.

B Cell Malignancies:

• CD37 is highly expressed on B cell malignancies such as non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL). It serves as a potential therapeutic target for these cancers. Monoclonal antibodies targeting CD37, such as otlertuzumab, have been developed to treat B cell malignancies by inducing antibody-dependent cellular cytotoxicity (ADCC) and apoptosis in malignant cells.
• Targeting CD37 with antibody-based therapies is a promising approach, given its selective expression on B cells and its involvement in B cell survival.

Autoimmune Diseases:

• Altered expression or function of CD37 has been implicated in autoimmune diseases. For example, CD37-deficient mice show enhanced T cell responses and an increased susceptibility to autoimmune conditions, suggesting that CD37 plays a regulatory role in preventing inappropriate immune activation.
• CD37 may influence the balance between immune activation and tolerance, making it relevant in the study of autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus.

Infectious Diseases:

• CD37 is involved in the immune response to infections, particularly through its role in organizing immune cell interactions. Its modulation may affect the ability of the immune system to respond to pathogens, although more research is needed to fully understand its role in infectious diseases.

Immunotherapy:

• Given its specific expression on B cells and its role in immune regulation, CD37 is a potential target for immunotherapy. Therapeutic antibodies targeting CD37 are being explored for their potential to treat both cancer and autoimmune diseases by modulating immune cell function.

Summary

CD37 is a key member of the tetraspanin family, with important roles in organizing immune cell membrane proteins, regulating B cell responses, and modulating immune signaling. Its involvement in B cell maturation, antigen presentation, and immune homeostasis underscores its significance in the immune system. Clinically, CD37 is implicated in B cell malignancies such as non-Hodgkin lymphoma and chronic lymphocytic leukemia, where it serves as a therapeutic target. Additionally, CD37 plays a role in autoimmune diseases and immune regulation. Understanding the structure and function of CD37 provides valuable insights into its potential as a therapeutic target in cancer and immune-related disorders.