Fascinating Aspects of Glycobiology—Part 14 (Glycan Functions)

Larry A. Law

The diverse roles glycans play in the body are simply astounding. As communication sugars, they represent the language of life. That is impressive enough by itself, but they do much more. Glycoproteins hold cells together. When they perform this function, they are referred to as cell adhesion molecules (CAMs). They govern the stickiness of cells—how they clump or align and stick together. When adhesion fails in cancer cells, scientists call this metastasis. 

Cell Differentiation

Adult stem cells are the cells that replace and regenerate damaged cells. Stem cells can morph into any cell needed by the body. This differentiation involves the construction of different cell-surface sugar structures on their cell membrane. Remember that each cell has a copy of all the DNA necessary to make any cell within the body. It just depends upon which genes get read as to what part of the blueprint gets built. Even as cells grow and mature, their glycoproteins can change, indicating their age and maturity. 

Transport Mechanism

Most plasma proteins (proteins in the blood that carry things around the body), like transferrin and mannose binding lectins (MBLs), hormones like insulin, thyroid stimulating hormone (TSH), follicle stimulating hormone (FSh), human chorionic gonadotropin (hCG), parathyroid hormone (PTH), and some enzymes like alkaline phosphatase, are all glycoproteins. Seventy percent of all human protein is glycoprotein. So, these sugars are attached to proteins and lipids floating virtually everywhere in the body. They perform a logistical function similar to an envelope being sent through the postal system. They make sure the needed contents get from the sender to the receiver quickly and effectively; in this way, the body can perform all of its various regulatory functions to maintain balance within the ever-changing body.

​Signal Transduction

Glycans are involved in all aspects of cell-to-cell communication. Signal transduction, notch signaling, ligand-receptor binding, and fertilization are all examples of this function. Glycoprotein cell receptors are composed of cell-surface sugar structures that serve as gateways or lock/key systems controlling access to the cell. Outside molecules dock on these receptors. When they successfully dock, a message is transmitted from the outside to the inside of the cell. A metabolic pathway of chemical reactions associated with the internal structure of the glycoprotein is opened up and turned on. This results in genetic instructions being transcribed from genes inside the nucleus. The cell reads these instructions and takes the actions to respond and handle the request properly. The hormone insulin is a great example. It flows from the pancreas through the blood and docks on an insulin receptor on destination cells. The hormone acts like a key to turn the cell receptor lock and open the door so the cell can cause cellular machinery to run and handle blood sugar appropriately. The picture below is an example of a specific type of signal transduction called Notch signaling. The notch protein spans the cell membrane with part of it inside and part outside. The part outside has the glycans. A ligand glycoprotein from the sending cell binds to the receiving (bottom) cell via its glycoprotein sugars (the notch). This binding causes a conformational change (a physical bending) in the antenna structure. 

Notch Signaling Details

Inside the receiving cell, the protein sheath covering otherwise hidden proteins has been pulled up due to the conformational change, and enzymes read the newly exposed proteins. The conformational change involves a twist and bending of the antenna structure, which is caused by the electromagnetic forces generated when the sender's molecules bind to the receiver's antenna. This structural change in the glycoprotein antenna exposes the proteins underneath the sleeve in the same way pulling up your long-sleeved shirt exposes your arm. Enzymes can then read the exposed proteins. Molecules within the cytoplasm are then directed to enter the nucleus and transcribe the targeted gene. The instructions from the gene are read, and action is taken in accordance with those instructions. DNA is transcribed into mRNA, and glycoproteins are built in the ribosomes (R), Golgi apparatus (GA), and the endoplasmic reticulum (ER) to convert the instructions into actionable molecules. This is how gene expression takes place. Genes are turned on or expressed by events and forces outside the cell that appropriately bind to the cell. If there weren't a glycoprotein unique to the event, then nothing would happen. There has to be a lock and a key capable of fitting that lock for action to be initiated within the cell. 

Bacterial Infection, Viral Attachment, and Immune System Function

Immune function relies heavily on glycoproteins for recognition, repair, and destruction processes like apoptosis. All immunoglobulins (antibodies) are glycoproteins. Selectins are glycoproteins that regulate inflammation and cytokine storms. The rolling action of immune system defense cells like macrophages is regulated by glycoproteins. In the picture below, circulating white blood cells like macrophages patrol the bloodstream; there, they sense glycoproteins being extended from endothelial cells on the interior wall of the blood vessel in the inflammatory region. Running into these glycoproteins induces a rolling action that slows the macrophage until it can adhere to a glycoprotein on one of the endothelial cells. The macrophage then squeezes through the juncture between endothelial cells as it follows the cytokine chemical signals emitting from the damaged tissue, just like a dog on the hunt. The macrophage then does battle with foreign invaders or engages in clean-up at the wound site.  

Let's now look briefly at how the science of glycobiology accounts for viral infection. Bacterial infection results from the lectins (glycoproteins) on the surface of bacteria attaching to glycoproteins on the surface of cells. Urinary tract infections result from E. coli bacteria attaching to the epithelial cell lining of the urinary tract. Almost all bacteria have lectins, and the terminal sugar on those lectins is mannose. This explains how macrophages can identify and destroy bacteria. Mannose binding lectins (MBL) are a transport plasma protein with a high affinity for mannose, fucose, and N-acetylglucosamine sugar residues that are usually found on invading microorganisms. MBL plays a major role in the activation of the complement pathway of the immune system. This method of activation is why the immune system easily detects foreign antigens associated with invading microorganisms. Free-floating mannose can also induce this same MBL-type of action without turning on the complement immune system. This is why supplementing mannose is such a good idea for creating and supporting an active immune system.