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. A human has tens of thousands of proteins in their body at any given moment in time. Each of these proteins has its 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. Large polypeptide chains can be created by forming peptide bonds between the amino and carboxyl groups on 2 different amino acids. Every protein can be described according to its primary structure, secondary structure, tertiary structure, and quaternary structure is present. In brief, the primary structure is the linear chain of amino acids. The secondary structure comprises regions stabilized by hydrogen bonds between atoms in the polypeptide backbone. Tertiary structure is the protein's 3-dimensional shape determined by regions stabilized by interactions between the side chains. Quaternary structure is the association between 2 or more polypeptides, but not every protein has a quaternary structure.[1][2][3][4]

Fundamentals

While interactions between the backbone constituents form the secondary structure, the tertiary structure is the overall 3-dimensional shape formed by the interactions of the side chains of the various amino acids. The side chains of amino acids are often called R groups. They can be polar, nonpolar, or charged, giving rise to amino acids with varying physical properties. The polar and charged amino acids are hydrophilic and can dissolve in water, whereas the nonpolar amino acids are hydrophobic and do not dissolve in water. The properties of amino acids also influence the protein's tertiary structure or overall shape.[5][6][7]

One type of interaction that plays a major role in the correct folding of a protein is the hydrophobic interaction. As a polypeptide folds into its correct shape, amino acids with nonpolar side chains usually cluster at the core of the protein, staying away from water. Once the nonpolar amino acids have formed the nonpolar core of the protein, weak van der Waals forces stabilize the protein. Furthermore, hydrogen bonds and ionic interactions between the polar, charged amino acids contribute to the tertiary structure. These are all weak interactions in the cellular environment, but their cumulative effect helps give proteins their unique shape. Disulfide bridges, covalent bonds formed between 2 cysteine residues, further reinforce the shape of a protein. Disulfide bridges form when the sulfhydryl groups of 2 cysteine residues come into close contact because of protein folding. Covalent bonds are not a weak interaction.

Primary structure determines tertiary structure and protein function. The most important proof of this came from experiments showing that the denaturation of a protein is reversible. Certain proteins denatured by heat, extreme pH, or denaturing reagents regain their native structure and original biological function when conditions return to the state in which the native conformation of the protein is stable. For example, ribonuclease denatures in urea and mercaptoethanol, 2 denaturing reagents. The disulfide bridges break apart in the reducing environment. Ribonuclease regains its native conformation after the removal of urea and mercaptoethanol. This is just 1 of the many examples showing that primary structure determines the tertiary structure.

Most proteins probably go through several intermediate structures on their way to the most stable shape, and there is no way of knowing these intermediate forms by just looking at the final, folded protein. Crucial to the folding process are chaperonins, protein molecules that assist in the proper folding of other proteins. Chaperonins keep the protein away from the disruptive chemical conditions in the cytoplasmic environment and allow the polypeptide to fold spontaneously. Defects in protein folding provide the molecular basis for several genetic disorders.

Clinical Significance

The structure of proteins determines their function. Therefore, an incorrectly folded protein in the human body can have catastrophic effects on the individual. The tertiary structure of a protein can be affected by misfolding of a protein or by a change in the primary structure of the protein. Misfolding of a protein can lead to type 2 diabetes, Alzheimer disease, Huntington disease, and Parkinson disease. For all these listed conditions, a soluble protein normally secreted from the cell is misfolded and secreted as an insoluble protein. This insoluble form is called an amyloid fiber, and all the diseases that result from this condition are collectively known as amyloidoses.

Another way the tertiary structure of proteins can be incorrect is if a mutation in the gene encodes for a specific protein. One disease that is caused due to this reason is cystic fibrosis. Cystic fibrosis is an inherited disorder in which mucus becomes thick and sticky. Normally, the mucus created by epithelial cells is watery and acts as a lubricant to protect tissues. However, the thick and sticky mucus does not move easily and can cause infections. Some of the other symptoms include difficulty absorbing nutrients for children and infertility for men. One misfolded protein causes all of these issues. Cystic fibrosis occurs because of mutations in the gene that makes a protein called cystic fibrosis transmembrane regulator (CFTR). A person with cystic fibrosis produces abnormal CFTR protein and sometimes no CFTR protein. This, as stated, causes the body to make thick, sticky mucus instead of the thin, watery kind.[8]

The primary structure of a protein determines its secondary and tertiary structure, and it can be mutated in many ways. Some of these altering mechanisms include mutations in the gene which can be brought about by environmental factors such as ultraviolet (UV) radiation or by errors in DNA replication. Furthermore, the primary structure can be incorrect if the translation process on the ribosome does not go entirely correctly. It is important to understand that all structure and function of a protein depends on its primary structure; if incorrect, it can lead to sometimes devastating effects on the human body.