Biochemistry, Tertiary Structure, Protein


Article Author:
Ibraheem Rehman


Article Editor:
Salome Botelho


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Carrie Smith


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James Hughes
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Tehmina Warsi


Updated:
4/21/2019 9:20:05 PM

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. By forming peptide bonds between the amino and carboxyl groups on two different amino acids, large polypeptide chains can be created. Every protein can be described according to its primary structure, secondary structure, tertiary structure, and quaternary structure is present. 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.[1][2][3][4]

Fundamentals

While the secondary structure is formed by interactions between the backbone constituents, the tertiary structure is the overall three-dimensional shape that is 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, and this gives 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 tertiary structure or overall shape of the protein.[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 two cysteine residues, further reinforce the shape of a protein. Disulfide bridges form when the sulfhydryl groups of two 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 denaturation of a protein is reversible. Certain proteins denatured by heat, extreme pH, or denaturing reagents will regain their native structure and original biological function when conditions return to the state in which the native conformation of the protein was stable. For example, ribonuclease denatures in the presence of urea and mercaptoethanol, two 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 one of the many examples that have shown 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 a number of 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 of these listed conditions, a soluble protein that is 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 collective known as amyloidoses.

Another way in which the tertiary structure of proteins can be incorrect is if there is a mutation in the gene that 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 so easily and can cause infections in the body. 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 at all. 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 process of translation 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 and if it is incorrect, it can lead to sometimes devastating effects on the human body.


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Biochemistry, Tertiary Structure, Protein - Questions

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Integral membrane spanning proteins have tertiary structure with which of the following characteristics?



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Which of the following does not contribute to the tertiary structure of a protein?



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If a protein was exposed to a reducing environment, which of the following would most likely be affected?



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Biochemistry, Tertiary Structure, Protein - References

References

Aprahamian ML,Lindert S, Utility of Covalent Labeling Mass Spectrometry Data in Protein Structure Prediction with Rosetta. Journal of chemical theory and computation. 2019 Apr 4;     [PubMed]
Banach M,Konieczny L,Roterman I, Secondary and Supersecondary Structure of Proteins in Light of the Structure of Hydrophobic Cores. Methods in molecular biology (Clifton, N.J.). 2019;     [PubMed]
Bayse CA,Pollard DB, Conformation dynamics of cyclic disulfides and selenosulfides in CXXC(U) (X = Gly, Ala) tetrapeptide redox motifs. Journal of peptide science : an official publication of the European Peptide Society. 2019 Mar 14;     [PubMed]
Bleiholder C,Liu FC, Structure Relaxation Approximation (SRA) for Elucidation of Protein Structures from Ion Mobility Measurements. The journal of physical chemistry. B. 2019 Apr 4;     [PubMed]
Rittle J,Field MJ,Green MT,Tezcan FA, An efficient, step-economical strategy for the design of functional metalloproteins. Nature chemistry. 2019 Feb 18;     [PubMed]
Snead D,Eliezer D, Intrinsically disordered proteins in synaptic vesicle trafficking and release. The Journal of biological chemistry. 2019 Mar 8;     [PubMed]
Gligorijević N,Minić S,Robajac D,Nikolić M,Ćirković Veličković T,Nedić O, Characterisation and the effects of bilirubin binding to human fibrinogen. International journal of biological macromolecules. 2019 May 1;     [PubMed]
Molinski SV,Shahani VM,Subramanian AS,MacKinnon SS,Woollard G,Laforet M,Laselva O,Morayniss LD,Bear CE,Windemuth A, Comprehensive mapping of cystic fibrosis mutations to CFTR protein identifies mutation clusters and molecular docking predicts corrector binding site. Proteins. 2018 Aug;     [PubMed]

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