DPP4 - dipeptidyl peptidase 4 |Elisa - Clia - Antibody - Protein

Background

Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a transmembrane glycoprotein and serine protease that plays a significant role in regulating glucose metabolism, immune function, and cell signaling. It is expressed on the surface of various cell types, including epithelial cells, endothelial cells, and immune cells such as T cells and B cells. DPP4 is widely known for its role in glucose homeostasis through its enzymatic activity, where it deactivates incretin hormones like glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones promote insulin release in response to meals, and their inactivation by DPP4 reduces insulin secretion, thereby impacting blood sugar levels.

Beyond its metabolic functions, DPP4 also participates in various immune regulatory pathways. As CD26, it is involved in T-cell activation and co-stimulation. DPP4 is linked to inflammatory processes and certain cancers, particularly due to its enzymatic activity and role in regulating immune responses. Additionally, the soluble form of DPP4 (sDPP4), which circulates in the plasma, plays a role in systemic metabolic and immune regulation.

DPP4 is a target of pharmacological inhibition, primarily for the treatment of type 2 diabetes mellitus (T2DM). DPP4 inhibitors (or gliptins) are a class of antidiabetic drugs that work by preventing the inactivation of incretin hormones, thus enhancing insulin secretion and lowering blood glucose levels. The role of DPP4 in various diseases, including cancer, cardiovascular diseases, fibrotic diseases, and autoimmune disorders, makes it a molecule of high therapeutic interest beyond its established role in glucose metabolism.

Protein Structure

DPP4 is a single-pass type II transmembrane protein consisting of 766 amino acids. Its structure can be divided into several key regions that contribute to its enzymatic and signaling functions:

Cytoplasmic Domain:

• The cytoplasmic tail of DPP4 is very short, consisting of only 6 amino acids. This region does not play a significant role in the protein's enzymatic function but is important for anchoring the protein to the cell membrane.

Transmembrane Domain:

• The transmembrane region spans the cell membrane, anchoring the protein into the cell membrane. This single-pass domain helps position the extracellular catalytic domain in the correct orientation for enzymatic function.

Extracellular Domain:

The majority of the DPP4 protein lies outside the cell and consists of an extensive extracellular domain responsible for its enzymatic activity. This domain includes:

• Catalytic Region: The core of DPP4’s activity is the serine protease domain, located between residues 508 and 766. This region is responsible for its dipeptidyl peptidase activity, which cleaves N-terminal dipeptides from substrates containing proline or alanine at the second position. The key residues involved in the catalytic triad include Ser630, Asp708, and His740.
• Beta-propeller domain: DPP4 has an N-terminal β-propeller structure that provides a stable scaffold for substrate binding. The eight-bladed β-propeller folds into a circular arrangement, and this domain also mediates interactions with other proteins and substrates. Notably, this domain can bind adenosine deaminase (ADA), suggesting a role in immune cell interactions.
• Glycosylation Sites: DPP4 is highly glycosylated, which aids in protein folding, stability, and interactions with other molecules. Glycosylation also affects the interaction between DPP4 and different ligands or substrates.

Dimerization:

• DPP4 exists predominantly as a homodimer on the cell surface, which is important for its stability and function. Dimerization enables the enzyme to properly orient its active sites for efficient catalysis. DPP4 can also exist in a soluble form (sDPP4) after being shed from the cell surface by proteolytic cleavage.

Classification and Subtypes

DPP4 belongs to the serine protease family and is classified under the prolyl oligopeptidase (POP) family. This family of enzymes primarily cleaves after proline residues, which distinguishes them from many other proteases.

While DPP4 (CD26) is the primary molecule of interest, several other related enzymes belong to the DPP family, including:

• DPP8 and DPP9: Enzymes that share homology with DPP4 but are localized intracellularly.
• DPP2 (FAP): Also known as fibroblast activation protein, this enzyme shares some functional characteristics with DPP4 but is primarily involved in tissue remodeling and fibrosis.

Each member of the DPP family has a distinct expression pattern and functional role, though they share the ability to cleave dipeptides from the N-terminus of polypeptides.

Function and Biological Significance

DPP4 has several important physiological roles, most notably in:

Glucose Metabolism:

• The most well-characterized function of DPP4 is its role in glucose homeostasis. DPP4 degrades incretin hormones such as GLP-1 and GIP, which are responsible for stimulating insulin secretion from pancreatic β-cells. By inactivating these hormones, DPP4 limits insulin release, thereby regulating postprandial glucose levels. DPP4 inhibitors, such as sitagliptin and vildagliptin, work by blocking this enzyme, leading to prolonged incretin activity, increased insulin release, and better glycemic control in type 2 diabetes.

Immune Regulation:

• DPP4 (CD26) plays a role in T-cell activation and costimulation. It is involved in the T-cell receptor (TCR) signaling pathway and can interact with adenosine deaminase (ADA), a critical enzyme in purine metabolism, to modulate immune responses. DPP4’s role in the immune system extends to the regulation of T cell migration, cytokine production, and activation.

Cell Adhesion and Migration:

• DPP4 acts as a binding partner for extracellular matrix proteins and is involved in cell adhesion and migration. This role is particularly relevant in cancer biology, where DPP4 expression can influence tumor progression, metastasis, and the tumor microenvironment.

Endocrine and Cardiovascular Effects:

• In addition to its metabolic and immune functions, DPP4 influences cardiovascular function. It has been implicated in the regulation of blood pressure and vascular integrity, partly through its effects on GLP-1. Studies have shown that DPP4 inhibitors can have cardioprotective effects, making them valuable not only in diabetes management but also in reducing cardiovascular risk.

Soluble DPP4 (sDPP4):

• The soluble form of DPP4 (sDPP4) circulates in the bloodstream and retains enzymatic activity. Elevated levels of sDPP4 are observed in obesity, diabetes, and inflammatory conditions, and it may act as a marker for these metabolic and immune disorders.

Clinical Issues

• Type 2 Diabetes Mellitus (T2DM):
• DPP4 inhibitors are widely used in the treatment of type 2 diabetes. By inhibiting DPP4, these drugs increase the half-life of incretins, thus enhancing insulin secretion and lowering blood glucose levels. Drugs in this class include sitagliptin, saxagliptin, and vildagliptin. These medications are particularly useful because they have a low risk of hypoglycemia compared to other antidiabetic agents.
• Cancer:
• DPP4 has been implicated in the progression of various cancers, including colorectal cancer, lung cancer, and melanoma. DPP4’s role in regulating immune responses, adhesion, and cell migration contributes to its influence on tumor growth and metastasis. In some cancers, DPP4 acts as a tumor suppressor, while in others, its overexpression is associated with more aggressive disease.
• Cardiovascular Disease:
• Given DPP4’s involvement in glucose metabolism and inflammation, it has been linked to cardiovascular diseases (CVD). DPP4 inhibitors may provide cardiovascular benefits in patients with diabetes, but the precise mechanisms and clinical outcomes are still under investigation.
• Fibrotic Diseases:
• DPP4 is involved in tissue remodeling and has been linked to fibrotic diseases such as pulmonary fibrosis and liver fibrosis. Inhibiting DPP4 in these conditions could potentially reduce fibrotic activity, although more research is needed to fully understand this role.
• Autoimmune Diseases:
• DPP4 also plays a role in the immune system, influencing autoimmune disorders such as rheumatoid arthritis and multiple sclerosis. Altered DPP4 expression or activity can contribute to dysregulated immune responses in these conditions.

Summary

DPP4 (dipeptidyl peptidase 4) is a multifunctional enzyme with critical roles in glucose metabolism, immune regulation, cell adhesion, and cardiovascular health. As a serine protease, it regulates the activity of key hormones like GLP-1 and GIP, influencing insulin secretion and blood glucose levels. DPP4 inhibitors have become essential in managing type 2 diabetes. Beyond metabolism, DPP4 is involved in immune responses, tumor progression, and fibrotic diseases, making it a target for various therapeutic interventions. While the inhibition of DPP4 has clear benefits in diabetes treatment, its roles in cancer, cardiovascular disease, and autoimmune disorders remain active areas of research.