Introduction

Nearly every function in living beings depends on proteins. They account for 50% of the dry mass of cells and play a role in everything an organism does. There are many different types of proteins. Different proteins can play a role in speeding up chemical reactions, storage, defense, cell communication, movement, and structural support. Humans have tens of thousands of proteins in their bodies at any given moment in time. Each of these proteins has its own structure and function. They are known as the most structurally complicated biological molecules. As diverse as they can be, they are all made up of the same 20 amino acids. By forming peptide bonds between the amino and carboxyl groups on two different amino acids, large polypeptide chains can be created.[1]

Every protein can be described according to its primary structure, secondary structure, tertiary structure, and quaternary structure. In brief, primary structure is the linear chain of amino acids. Secondary structure is comprised of regions stabilized by hydrogen bonds between atoms in the polypeptide backbone. Tertiary structure is the three-dimensional shape of the protein determined by regions stabilized by interactions between the side chains. Quaternary structure is the association between two or more polypeptides, but not every protein has a quaternary structure.[2][3]

Fundamentals

The secondary structure arises from the hydrogen bonds formed between atoms of the polypeptide backbone. The hydrogen bonds form between the partially negative oxygen atom and the partially positive nitrogen atom. It is significant to point out that the only hydrogen bonds involved in secondary structure do not include any involving amino acid side chains. Most proteins have segments of their polypeptide chains that are either coiled or folded in patterns that contribute to the protein’s shape. Many of these coils and folds repeat so often that they have been given names. Two folds that are extremely common in biochemistry are the alpha-helix and the beta-pleated sheet.

The alpha-helix is a right-handed helical coil that is held together by hydrogen bonding between every fourth amino acid. Many globular proteins have multiple alpha-helical portions separated by long stretches of non-helical regions. Some fibrous proteins, including alpha-keratin, are almost completely comprised of alpha-helices. Fingernails and toenails are also made up of alpha-helices. Transmembrane proteins contain alpha-helices with specific hydrophobic properties allowing them to traverse membranes and be stable within the cell membrane. Outside the membrane, the transmembrane proteins adopt a non-helical structure and many times the alpha-helix is broken by a proline residue.

The other common secondary structure is the beta-pleated sheet. In this structure, two different regions of a polypeptide chain lie side by side and are bound by hydrogen bonds. They make up the core of many globular proteins. The two types of beta-pleated sheets are parallel beta-pleated sheets and antiparallel beta-pleated sheets. The end of a polypeptide chain can either be the N-terminus or the C-terminus. The N-terminus is the end that contains the free amino group, and the C-terminus is the end that contains the free carboxyl group. If two beta-strands run in the same direction, then it is a parallel beta-pleated sheet, and if they run in opposing directions, then it is an antiparallel beta-pleated sheet.

Another less commonly known secondary structure is the beta-barrel. This structure is composed of antiparallel beta-strands, and it is twisted and coiled into a barrel so that the first strand hydrogen bonds to the last strand. Many times, beta-barrels can be found in proteins that span the membrane. One common example is aquaporins, which selectively allow water molecules in and out of a cell while preventing the passage of other solutes and ions. Also, it is important to note that the hydrogen bonds between the binding atoms are weak, but the summation of all the hydrogen bonds allows the structure to maintain its shape.

Clinical Significance

Changes in protein structure can lead to a variety of diseases. The secondary structure of a protein can be altered by either a mutation in the primary sequence of amino acids that make up the protein or by extreme conditions that force the proteins to denature or lose their shape. Prion diseases, also known as spongiform encephalopathies, and Amyloidosis are two classes of disease involving changes in the secondary structure of proteins. Both involve the misfolding of proteins into Beta sheets, and the presence of these proteins leading to tissue damage. If even one amino acid is changed in the primary sequence of a protein, the secondary structure of a protein can be drastically affected. Most genetic diseases can be linked back to a protein that does not have the structure it should. One such genetic disease is a sickle-cell disease, in which one glutamic acid amino acid is replaced with a valine amino acid. [4]

Spongiform Encephalopathies

Four spongiform encephalopathies to be aware of are: Creutzfeldt- Jakob disease, variant Creutzfeldt- Jakob disease due to bovine spongiform encephalopathy, Kuru, and fatal familial insomnia. The pathophysiology of prion diseases involves the conversion of normal cellular Prion protein (PrPc) from a mostly alpha-helical structure into a disease-causing form, with a beta pleated secondary structure, known as PrP scrapies (PrPsc). The Beta- pleated form is nondegradable and engages in a cycle causing the conversion of normally folded prion protein in the pathologic misfolded form. The pathologic form causes damage to neurons and glial cells, leading to the formation of intracellular vacuoles. The conversion itself can be sporadic, inherited, or transmitted. [5]

The most common prion disease is Creutzfeldt- Jakob disease. The disease itself is usually sporadic but can occur due to exposure to human tissue infected with prions. Variant Creutzfeldt- Jakob disease is related to consumption of meat from cattle having a prion disease known as bovine spongiform encephalopathy or mad cow disease. Fatal familial insomnia is due to an inheritance of a mutated form of prion protein and leads to sever insomnia as well as an exaggerated startle response. Kuru is a transmitted form of prion disease noted in tribal populations that practice cannibalism.[6][7][8]

Amyloidosis

Amyloidosis can be classified as systemic, involving many organ systems, or localized to a single organ.

Systemic amyloidosis can further be classified as primary or secondary amyloidosis. Primary amyloidosis specifically involves deposition of AL amyloid, derived from misfolded immunoglobulin light chains.  Secondary amyloidosis involves deposition of AA amyloid, which is derived from misfolded serum amyloid-associated protein (SAA). Serum amyloid- associated protein is classified as an acute-phase reactant and is increased in chronic inflammatory states, such as those in neoplastic states, and in Familial Mediterranean Fever (FMF). Increased levels of the protein can lead to its deposition as AA amyloid systemically. The clinical picture of systemic amyloidosis is widespread due to the systemic nature of the disease. [9][10]

A variety of forms of localized amyloidosis exist. One to be aware of is Alzheimer's disease. 

Alzheimer's disease involves the deposition of Beta-amyloid in the brain, leading to the formation of amyloid plaques. This misfolded protein is derived from Beta-amyloid precursor protein, the gene for which can be found on chromosome 21. A large proportion of patients with Down Syndrome, or trisomy 21, develop early-onset Alzheimer's disease. [11][12]

Sickle Cell Disease 

As stated, a slight change in the primary structure of a protein can lead to changes in the protein’s shape and function. Sickle-cell disease is an inherited blood disorder that is caused by the substitution of one amino acid for another. A nonpolar valine is substituted for a charged glutamic acid at the sixth amino acid position in the structure of hemoglobin- commonly referred to as an E6V mutation. Hemoglobin is the iron-containing oxygen transport protein in red blood cells, whose function is to transport oxygen from the lungs to the tissues. This protein is composed of four polypeptide chains, two of which are alpha-subunits and two of which are beta-subunits. Sickle-cell hemoglobin has normal alpha-subunits, but their beta-subunits are abnormally folded. This abnormal shape leads to hydrophobic reactions that lead to aggregation into a fiber and greatly reduce the capacity for oxygen transport. Furthermore, the fibers of sickle-cell hemoglobin deform red blood cells into a sickle shape.[13]

Pain is the most common symptom of sickle cell disease because the angular cells can clog small blood vessels, impeding blood flow. These symptoms can be reduced and sometimes avoided by drinking plenty of water, avoiding places with high altitude, and avoiding places with low oxygen levels. Unfortunately, the symptoms of the sickle-cell disease usually worsen with time. In the most extreme cases, even blindness can be caused due to a lack of oxygen in the eye. This example is a dramatic explanation of how a change in one amino acid can lead to a change in protein shape and have a devastating effect on the lives of certain individuals.[14]