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LET'S TALK LIFE-SCIENCE BIOCHEMISTRY

Suraj Prakash Sharma | Ekta Chotia

PROTEIN STRUCTURE
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4.      PROTEIN STRUCTURE

Protein is a polymer of amino acids. The amino acids are ligated by peptide bond during translation. Protein is folded, three dimensional structure and amino acids in a polypeptide chain or protein is called as residue. By convention, a chain of amino acid having less than 30 amino acid is known as peptide and more than 100 amino acids in a chain is known as poly peptide. The oligopeptide refers to a chain of protein having 30-100 amino acids.

4.1.         Primary structure

It is a linear chain of polypeptide or protein. During translation, it is formed by covalent or peptide bonds. One end of polypeptide is called C-terminal or carboxy terminal while other end is called amino terminal (N terminal). During translation, polypeptide chain grow in N terminal to C-terminal. Amino acid sequence of protein is unique.

4.2.         Secondary structure

Secondary structure is formed because of hydrogen bonding between the alpha NH2 group and alpha carboxilic group. Based on the nature of hydrogen bonding (whether intramolecular or intermolecular), Pauling and Corey (1951) identified two regular types of secondary structure in proteins : alpha helix ( \alpha-helix) and beta pleated sheet ( \beta-pleated sheet).  These secondary structure have regular geometry and specific value of  \varphi and \phi  angle.

4.2.1.     Types of secondary structure

Helical structure : It is formed when a polypeptide chain is twisted in a manner that each of its C2 atoms assume same bond angle. Helix is a coiled structure.

4.2.1.1. \alpha-Helix

The helix is a coiled structure. It is not linear like primary structure of protein. Pitch is a feature of a helix. Pitch is defined as vertical rise of helix per turn. With x-ray diffraction studies, Pauling and Corey (1951) found that a polypeptide chain with planar peptide bonds can form a right-handed helical structure by simple twists about the \alpha-carbon-to-nitrogen and the \alpha-carbon-to-carboxyl carbon bonds. The helix is so named because of the mobility of a-carbon atoms.

The \alpha-helix is stabilized by hydrogen bonds between the NH and CO groups of polypeptide’s main chain. The CO group of each amino acid is hydrogen-bonded to the NH group of the amino acid that is situated four residues ahead in the linear sequence . Thus, all the main chain CO and NH groups participate in hydrogen bonding.

There are 3.6 amino acid residues per turn of the helix. The pitch is 5.4 A° for the alpha helix. For a polypeptide made from L-\alpha-amino acid residues, the a-helix is right handed with torsion angles \phi –57° and \psi –47°. (An \alpha-helix of D-\alpha-amino acid residues is the mirror image of that made from L-amino acid residues: It is left handed with conformation angles \phi 57°, \psi 47°, and n-3.6. The pitch is same for both the L-amino acid and D-amino acid).

Many globular proteins contain short regions of such \alpha-helices, and the transmembrane portion of a protein is usually \alpha-helices. In a helix, R group is projected outside because R group is more bulky so not present inside the helix.

Keratin and collagen are almost entirely alpha helical in structure. The charged amino acid destabilizes the \alpha-helical structure and beta sheet and hydrophobic side chain are compatible with the formation of alpha helices and beta pleated sheet.

In aqueous environment, an isolated \alpha-helix is usually not stable on its own. The basic structural unit of \alpha-keratin usually consists of three right-handed helical polypeptides in a left-handed coil that is stabilized by cross linking disulfide bond.

4.2.1.2.   Amino acids affecting a-helical structure

  1. A prolyl reisdue has its a-N atom in a rigid ring system and cannot participate in a-helical structure . Proline is called as helix breaker and creates a sharp bend in the helix.
  2. A long repeat  of aspartyl and/or glutamyl residues can destabilize a-helical structure because the negatively-charged side chains repel one another (electrostatic repulsion), and the forces of repulsion are greater than those of hydrogen bonding.
  3. A long sequence  of isoleucyl residues disrupts  helix formation, because of steric hindrance imposed by their bulky R groups.
  4. Glycine, with a small hydrogen atom as a R group, is another destabilizer. The lack of a side chain on glycine allows for a great degree of rotation about the amino acid’s a-carbon. Thus conformations other than a helical bond angles are possible for glycine  which destabilize the helix.

4.2.2.     \beta sheet :

\beta sheet are formed by hydrogen bonding, between the alpha carboxylic (CO) group of amino acid with the alpha amino group (–NH) is adjacent amino acid. It exist in antiparallel and parallel form. Antiparallel \beta sheet are more stable. \beta Sheets are common structural motifs in proteins. In globular proteins, they consist of from two to as many as twenty two polypeptide strands. In \beta-sheet hydrogen bonds are more or less one. In antiparallel \beta-sheet hydrogen bonds are more than one and in parallel it is less than one. Parallel and antiparallel \beta-sheets are connected by loops.

The energetically preferred dihedral angles \phi, \varphi are –135° and 135° respectively for \beta sheet. However the \phi and \varphi angles are –140° and 135° for antiparallel \beta Sheet and - 120° and 115° for parallel \beta sheet.

Globular proteins consist of an average, ~31% a helix and ~28% b sheet. The remaining polypeptide segments of protein are said to have a coil or loop conformation.

Silk fibroin is one example of a protein that has the antiparallel pleated sheet structure. It is a member of a class of fibrillar proteins called \alpha-keratin.

4.2.3.     Turns :

Turns are secondary structure. They are reversal in nature i.e. they reverse the direction of polypeptide chain. In turn three amino acids participate. Turn is stabilized by hydrogen bonding between the CO of residue ‘n’ and the NH of residue n + 3. Proline amino acid usually present in turn at position number two.

Only helix can form turn, proline amino acid is sometimes known as “helix breakers”. Because they disrupts the regularity of the a helical backbone conformation.

Types of turn

Basically turn are of two types designated as I and II. Type I turn contain all residues in position n  to n + 3. In type I turn proline is present at position number two and the 3rd position is acquired by any amino acid..

Type II turn contain proline at similar position to type I turn, but the third amino acid in type II turn is Glycine.

  • Turn helps to form secondary structure and provide stability to protein, maintain its structure.
  • Some aromatic amino acids that participate in \alpha helix formation are tryptophan, tyrosine and phenylalanine. The Methionine, Glutamate, Leucine and alanine also has strong tendency to form a helix.  Amino acids that form b sheet includes valine, isoleucine, and proline. Among these amino acids, methionine has the highest tendency to form a helix and valine has highest tendency to form \beta sheet. Minimum seven amino acids are required to form \alpha helix and six amino acids are require to form \beta sheet.

4.3.         Super secondary structure

They are also called as motif, it is a folding pattern involving two or more elements of secondary structure. Motif provides function to domain. They are of different types simplest among them with specific function consists of two alpha-helices joined by a loop region.

Examples of motif are :

4.3.1.     DNA binding motif :–

A motif specific for calcium bending and is present in paravalbumin, calmodulin, troponin c, and the proteins that bind calcium and thereby regulate cellular activities.

4.4.         Tertiary structure of protein -

Tertiary structure of protein is a three dimensional structure of protein. Tertiary structure is formed during protein folding. Protein folding involves the interaction of diverse R group (side chain) of amino acids. Various forces are involve in formation of tertiary structure.

                1.            Hydrogen bonding

                2.            Disulphide bond

                3.            Electrostatic or Ionic bond

                4.            Hydrophobic bonding

The protein can be classified broadly based upon the tertiary structure.

(A)  Globular proteins have a core of hydrophobic amino acid residue and a water exposed, polar, charged hydrophilic residue on surface. This arrangement makes protein soluble in water and stable in conformation. The disulphide bond  increase the stability of protein. The protein folding process in achieved with help of chaperons

4.4.1.     Importance of tertiary structure

Protein specific function depends on tertiary structure. If this is disrupted, the protein is said to be denatured and show loss its activity. eg : Denature enzymes loss its catalytic power with denatured antibodies can no longer bind with antigen. A mutation in the DNA may alter the amino acid in protein which resulted into improper folding. Misfolding protein fail to perform its function.

4.4.2.     Some of examples includes :

Cystic fibrosis is caused because of failure of the mutant CFTR protein to its target place in plasma membrane.

Diabetes is caused by improper folding of mutant versions of : V2 the vasopressin (ADH) receptor and aquaporin.

Hypercholesterolemia is caused by failure of mutant low density lipoprotein receptors to reach the plasma membrane.

Osteogenesis imperfecta is caused by failure of mutant type one collagen molecules to assemble correctly.

Mutant protein form inclusion bodies that is aggregation of insoluble protein caused by nonfunctional deposits.

4.5.         Quaternary structure :

Quaternary structure is formed by more than one polypeptide. A protein with multiple polypeptide chains is multimeric in nature . Multimeric protein  exhibit quaternary structure.

One       Subunit          Monomer

Two       Subunit          Dimer

Three    Subunit          Trimer

Four       Subunit         Tetramer

More than four–Multimers Changes in conformation within individual subunits can cause change in quaternary structure.

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