BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 5. STRUCTURE, PROPERTIES, AND FUNCTIONS OF PROTEINS

5.3. Formation of the Three-Dimensional Protein Structure in the Cell

5.3.3. Diseases Associated with Protein Misfolding

Calculations have shown that only a small fraction of theoretically possible polypeptide chain variants can adopt a single stable Spatial Structure. Most Proteins can instead assume A large number of Conformations with approximately the same Gibbs Free energy while exhibiting different properties. The Introduction/19.html">Primary Structure of most known proteins, shaped by evolution, ensures the exceptional stability of a single conformation.

However, under altered conditions, certain Water-soluble proteins can acquire conformations of poorly soluble, aggregation-prone molecules that form fibrillar deposits in Cells known as amyloid (from Lat. *amylum* - starch). Like starch, amyloid inclusions stain with iodine in tissue samples. This can occur As a result of:

✵ overproduction of certain proteins, leading to an increase in their intracellular concentration;

✵ the entry into The Cell, or formation within it, of proteins capable of influencing the conformation of other protein molecules;

✵ activation of normal cellular protein proteolysis, resulting in The formation of insoluble, aggregation-prone fragments;

✵ point Mutations within the Protein Structure.

The deposition of amyloid in Organs and Tissues disrupts cellular Structure and function, leading to degenerative changes and the proliferation of Connective Tissue or glial cells. This gives rise to diseases known as amyloidoses. Each type of amyloidosis is characterized by a specific type of amyloid. Over 15 such diseases have been described to date.

Alzheimer's disease is the most common among the $\beta$-amyloidoses of The Nervous system. As a rule, it affects elderly individuals and is characterized by progressive memory impairment and complete personality degradation. $\beta$-amyloid—a conformational variant of a normal human protein—is deposited in Brain tissue. It is formed from a large precursor via partial proteolysis and is synthesized in many tissues. Unlike its normal precursor, which is rich in $\alpha$-helical regions, $\beta$-amyloid possesses a secondary $\beta$-pleated sheet structure, aggregates to form insoluble fibrils, and is resistant to Proteolytic Enzymes.

The causes of protein misfolding in brain tissue remain unclear and await elucidation. It is possible that Aging leads to a decline in the synthesis of chaperones, which are responsible for forming and maintaining the native protein conformation, or to an increase in protease activity, thereby raising the concentration of conformation-altering proteins.

Prion diseases. Prions are a unique Class of proteins with infectious properties. Upon entering The Human Body or arising spontaneously, they can cause severe, incurable Central Nervous System disorders known as prion diseases. The term "prions" is derived from the acronym for "proteinaceous infectious particle".

The prion protein is encoded by the same Gene as its normal counterpart, meaning they share an identical primary structure. However, the two proteins differ in conformation: the prion protein is characterized by a high $\beta$-sheet content, whereas the normal protein is rich in $\alpha$-helical regions. Furthermore, the prion protein is resistant to proteases and, upon entering brain tissues, promotes The conversion of the normal protein into the prion form through Protein-Protein Interactions. This results in the formation of a so-called polymerization Nucleus composed of aggregated prion proteins, to which new molecules of the normal protein can attach. Consequently, their spatial structure undergoes the conformational rearrangements characteristic of prion proteins.

Hereditary forms of prion diseases caused by mutations in the protein structure are well documented. However, human infection with prion proteins is also possible, leading to fatal disease. For instance, kuru—a prion disease among the indigenous people of New Guinea—had an epidemic nature linked to traditional cannibalism within these tribes and the transmission of the infectious protein from person to person. With changes in their lifestyle, this disease has practically disappeared.

Today, interest in prion diseases has surged due to human infection via meat products derived from animals carrying prions that cause bovine spongiform encephalopathy (Creutzfeldt-Jakob disease). Although Human and Animal prion proteins differ only slightly, it was long believed that interspecies barriers hindered disease transmission. Recent findings, however, have shown that these barriers are not absolute, and the transmission of the disease from one species to another is theoretically possible. For example, about 40 cases of this disease were registered in Great Britain by mid-1999. Projections do not rule out the possibility of a prion disease epidemic in the next 10-15 years.