Introduction
Aglycosylated proteins are molecules, most commonly proteins, that lack the complex sugar structures, known as glycans, typically attached to them. These sugar chains are usually added to proteins after they are synthesized, a process called glycosylation. When this modification has not occurred, the protein is aglycosylated. Such molecules are found throughout biological systems and can arise naturally or be engineered.
The Importance of Glycosylation
Glycosylation is a widespread biological process where carbohydrate chains, or glycans, are attached to proteins after they are produced. This post-translational modification plays a role in various functions within the body. Glycans contribute to the proper folding of proteins and also influence their stability. They can act like “address labels,” guiding proteins to their appropriate locations within cells or throughout the body, and serve as “quality control stamps.”
These sugar structures also mediate how proteins interact with other cells and molecules, influencing cell-to-cell communication and recognition. Immunoglobulin G (IgG), a type of antibody, normally carries a glycan chain on its Fc region. This specific glycosylation is important for the antibody’s normal function, including its ability to interact with immune cells and participate in defense mechanisms.
Functional Consequences of Lacking Glycosylation
When a protein becomes aglycosylated, or lacks its typical sugar chains, it can experience changes in its properties and activity. The absence of glycans can reduce the protein’s stability, potentially leading to its quicker degradation. This alteration can also affect the protein’s three-dimensional structure, subtly changing its overall shape. Such structural changes can, in turn, modify how the protein interacts with other molecules and its biological activity.
For antibodies like Immunoglobulin G (IgG), the absence of the N-glycan at asparagine 297 (Asn297) in the Fc region has specific consequences. Aglycosylated IgG can no longer bind effectively to certain Fc gamma receptors (FcγRs), particularly FcγRIIb, which are involved in dampening immune responses. Instead, it may bind to other activating FcγRs, potentially leading to different or even enhanced immune responses.
Aglycosylation in Disease and Health
Naturally occurring aglycosylation of proteins can play a part in various health conditions. In some autoimmune diseases, the body produces antibodies, specifically Immunoglobulin G (IgG), that are missing their normal sugar chains in the Fc region. These aglycosylated IgG antibodies are not merely inactive but can actively contribute to the disease process. For example, in rheumatoid arthritis, a condition characterized by chronic inflammation of the joints, a higher proportion of aglycosylated IgG is observed.
These altered antibodies can promote inflammation and tissue damage by shifting the immune response towards pro-inflammatory pathways. They may bind to activating Fc receptors on immune cells, triggering the release of inflammatory molecules and contributing to the destructive processes seen in the joints. This natural occurrence of aglycosylated antibodies highlights how a subtle molecular change can drive disease progression rather than protecting the body.
Engineered Aglycosylation in Medicine
Scientists can deliberately engineer monoclonal antibodies to be aglycosylated, a strategy employed to achieve specific therapeutic effects. This biotechnological approach involves modifying the antibody’s structure to prevent the attachment of sugar chains, which can enhance or alter its immune-modulating properties. This is distinct from the naturally occurring aglycosylation seen in diseases. By carefully designing these antibodies, researchers can harness the functional consequences of lacking glycosylation for medical benefit.
One application involves enhancing antibody-dependent cell-mediated cytotoxicity (ADCC), an immune mechanism where antibodies mark target cells for destruction by immune effector cells. Aglycosylated antibodies can be engineered to have increased affinity for activating Fc gamma receptors (FcγRs), such as FcγRIIIa, found on natural killer (NK) cells. This enhanced binding can lead to a more potent activation of NK cells, resulting in a more effective attack against cancer cells. For instance, in cancer therapy, aglycosylated antibodies are being developed to efficiently clear tumor cells, representing a promising avenue for next-generation immunotherapeutics.