Insight Into The Animo Acid Sequence Biology Essay

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Introduction

"The bacterium E. coli produces more than 3,000 different proteins and human being produces 50,000- 100,000"(Nelson, et al, 2000). In both cases, each type of protein has a unique three- dimensional structure and this structure provides function.

Each type of protein also has a unique amino acid sequence. Many scientists suggest that the amino acid sequence plays a fundamental role in determining the 3D structure of the protein, and ultimately its function (Bhagavan, 2002). This statement can be understood by comparing various different amino acid sequences in different proteins. First, proteins with different functions always have different amino acid sequence. Second, thousands of human genetic diseases were caused due to the production of defective proteins and most of these proteins were defective because of a single change in their amino acid sequence (Nelson, et al, 2000). Hence, the altered sequence of amino acids in turn alters the 3D structure and ultimately its function.

Amino Acid Sequence Determines The Final Three- Dimensional Structure Of a Protein.

Primary structure is just the linear sequence of amino acids in a protein and by convention, the sequences are always written from the N­terminus to the C­terminus of the polypeptide chain (Nelson, et al, 2000). All higher levels of protein structure are determined by the primary structure.

Secondary structure refers to the local conformation of some part of polypeptide due to hydrogen bonding. It usually focuses on common regular folding patterns of the polypeptide backbone. The most stable structures are α helix and β sheets. (Hames et al, 2005). α helix is spiral in shape consisting of a backbone of peptide bonds with the specific R groups of the individual amino acids.

β conformation is the extended conformation of polypeptide chains. The backbone is extended into zig­zag polypeptide chains which can be arranged side by side to form a structure called β sheets, and hydrogen bonds are formed between them. (Source Becker, et al. 2007)

The three dimensional structure (tertiary structure) refers to the spatial arrangement of amino acids that are far apart in the linear sequence as well as those residues that are adjacent. It is the sequence of amino acid that determines the final three dimensional structures (figure 1). The polypeptide chain folds spontaneously so that the hydrophobic side chains are buried in the inner side and polar, charged side chains are on the surface. Once folded, the three dimensional biologically active conformation of the protein is maintained by hydrophobic interactions, electrostatic forces, hydrogen bonding, disulfide bonds etc. (Hames, et al, 2005)

As said earlier the final 3D structure of a protein is determined by its amino acid sequence but exactly how it determines is not yet understood in detail (Nelson, et al, 2000). However, the important proof for this statement came from the classic experiment carried out by Christian Anfinsen in 1950s. He showed that denaturation of some proteins are reversible. Some proteins denatured by heat, extremes of pH, etc… can return to their αβnative structure and their biological activities if returned to normal conditions and this process is called as renaturation.

In 2000, Nelson and Cox say the entire polypeptide chain of a purified ribonuclease can be freed from its folded conformation by treating with concentrated urea solution containing a reducing agent. The reducing agent breaks the four disulfide bonds resulting in eight Cys residues and the urea disrupts the hydrophobic interactions, thus losing its catalytic activity. But when the urea and reducing agent are removed, the freed ribonuclease spontaneously refolds into its correct tertiary structure with restoration of its catalytic activity. The refolding is so accurate that the four disulfide bonds are re-formed in the same position in the renatured ribonuclease.

This classic example provided the first evidence that the information required to fold the chain into its native 3D structure are contained in the sequence of amino acids in a polypeptide chain. If not, when the denaturants are removed and brought back to normal conditions it would not refold and even if it does refolding would not be so accurate as discussed above. According to Bhagavan, 2002, beside the sequence of amino acid, other proteins are also involved in determining the final 3D structure of a protein.

Structural diversity of proteins & their associated functions

According to Nelson and Cox (2000), based on the higher levels of protein structures i.e. secondary, tertiary and quaternary structures, proteins can be broadly divided into two major groups.

Fibrous proteins: Here, the polypeptide chains are arranged in long strands or sheets. These proteins contain single type of secondary structure. It mainly provides support, shape and external protections. Certain fibrous proteins are helpful in the development of our modern understanding of protein structures and functions.

Globular proteins: Here, the polypeptide chains are folded into a spherical or globular shape. It consists of several types of secondary structures. Enzymes, transport proteins, motor proteins, and signaling proteins, etc. are some of the globular proteins which are discussed in later part.

A. Fibrous proteins (Structural proteins)-Adapted for structural function.

Structural proteins like α­keratin and collagen has properties which give strength and flexibility to the structures in which they occur. These proteins are insoluble in water and it is due to the high concentration of hydrophobic amino acid residues both the interior of the protein and on its surface.

α­Keratin- are found in hairs, wool, nails, horns, cytoskeleton, etc….

The keratin helix is a right handed helix and the helices are arranged as coiled coil. The two strands of keratin, oriented in parallel are wrapped about each other to form a supertwisted coiled coil. The supertwisting amplifies the strength of the overall structure, just as strands are twisted to make a strong rope. This strong rope like structures will provide the strength and structure to the tissues and organelles (Berg, et al, 2007).

Collagen- occurs in connective tissues like tendons, cartilage, matrix of bone, cornea of the eye, etc.

The collagen helix is a unique secondary structure. It is left-handed and has three amino acid residues per turn. Collagen is also a coiled coil, but one with distinct tertiary and quaternary structure. It means three separate polypeptides, called α chains (not α helix), supertwisted about each other. This twisting is right-handed helix of the α­chains which provides strength and support to cells (Berg, et al, 2007).

B. Globular proteins.

In a globular protein, different pieces of single or multiple polypeptide chains folded back on each other to generate a compact form of protein. The folding provides the structural diversity necessary for proteins to carry out a wide variety of biological functions

Transport proteins

It includes proteins like myoglobin, haemoglobin and so on. Myoglobin is a relatively small oxygen-binding proteins found in muscle cells. It stores oxygen as well as facilitates oxygen diffusion rapidly in contracting muscle tissues.

Figure4. Structure of Myoglobin and heme group (Source: Ophardt, 2003).

Figure5. Haemoglobin loading & unloading oxygen (Source: Campbell, et al, 2005).

Myoglobin is in 3D form containing a single polypeptide chain of 153 amino acids and the backbone of the myoglobin molecule is made up of eight straight segments of -helix interrupted by bends, some of which are β-turns. Most of the hydrophobic R-groups are in the inner side of the myoglobin whereas; other polar R-groups are located on the surface of the molecule. In addition, the heme or iron protoporphyrin group is noncovalently bonded to myoglobin which is essential for the biological activity, i.e. to transport oxygen (Nelson et al, 2000)

Haemoglobin has a quaternary structure as it is made up of four polypeptide chains; two α-chains and two β- chains, each with a heme group which facilitates oxygen transport in blood (Hames et al, 2005).

Enzymes.

It includes lysozyme, ribonuclease, and many more. Lysozymes are abundant in egg white and human tears that catalyze the hydrolytic cleavage of polysaccharides in the protective cell walls of some families of bacteria. It is named lysozyme because it has the property to lyse or degrade bacterial cell walls and serve as a bactericidal agent.

It is composed of 129 amino acid residues out of which only 40% of the polypeptide are in α-helical segments and some are β-sheet structures. The α-helices have the active site on the side of the molecule for substrate binding and catalysis. It also has four disulfide bonds which make the structure stable (Nelson, et al, 2000).

Ribonuclease is secreted by pancreas in the small intestine where it catalyzes the hydrolysis of certain bonds in the RNAs present in the ingested food. It contains 124 amino acid residues out of which only a little portion of the polypeptide chain are in α-helical conformation and major portion are the β-sheet segments. Four disulfide bonds are also present in the loops providing stability to the structure. (Nelson, et al, 2000)

Motor proteins.

The contractile forces of muscles and the movements of organelles and macromolecules are generated by the interaction of two proteins, myosin and actin.

Myosin has six-subunits; two heavy chains and four light chains. The heavy chains account for major part of the structure. At their carboxyl end, they are arranged as extended α helices, wrapped around each other and are left- handed coiled coil (Lodish, et al). At its amino end, each heavy chain has a globular domain containing a site for ATP hydrolysis. The light chains are associated with the globular domains.

In muscle cells, molecule of myosin aggregate to form thick filamentous structure which serves as the core of the contractile unit. Hundreds of myosin molecules are arranged with their fibrous tail to form a bipolar structure within a filament and their globular domains projecting from either ends. (Lodish, et al, 2004)

G- Actin. F- Actin.

Figure 7: Globular and Filamentous Actin. (Source: Campbell, et at, 2005).

Actin is abundant in almost all eukaryotic cells. In muscles, molecules of monomeric actin (G-actin) associate to form a long polymer (F-actin). The thin filament consists of F-actin and the protein troponin and tropomyosin. The filamentous parts assemble as successive monomeric actin molecules adding to one end and each monomer bind ATP, and then hydrolyse to ADP (Nelson, et al, 2000). However, the energy generated helps only in the assembly of the filaments and does not contribute to the overall muscle contraction. Each actin monomer in the thin filament can bind tightly and specifically to one myosin head group where the contractile forces are generated (Lodish, et al, 2004).

Signaling proteins

It includes peptide hormones such as insulin, glucagon, histamine, etc. These proteins help in the cell to cell communications in order to coordinate the growth and metabolism of cells.

"For instance, insulin receptor is a complex of two α and two β subunits held together by disulfide bonds. The polypeptide insulin binds to the extracellular face of the α­subunits. The receptor then undergoes a conformational change leading to the self phosphorylation of the cytosolic domain of the β subunits. Specifically hydroxyl groups in the side chains of certain tyrosine residues are phosphorylated, ATP being the phosphate donor. Now, these phosphorylated receptors help the cells to respond the hormones appropriately" (Hames, et al, 2005).

Conclusion

Generally, there are four recognized levels of protein structure and they are primary (sequence of amino acids), secondary (spatial arrangement of amino acids), tertiary (three-dimensional structure) and quaternary (multiple polypeptide chains) structures. The final 3D structure (native) is the most stable form of protein structure which is determined by the linear sequence of amino acids, but Nelson & Cox in 2000 says, how it determines is still not known in detail.

There are numerous proteins known and these proteins can be clubbed into two main groups, fibrous and globular proteins. Fibrous proteins, which serve mainly structural functions, have simple repeating elements of secondary structure. The two major types of secondary structure are the α-helix and β-conformation which are characterized by hydrogen bonding between peptide bonds in the polypeptide backbone.

Globular proteins have more complicated tertiary structures, often containing much secondary structure in the same polypeptide chain. Globular proteins can further be divided as transport proteins, enzymes, motor proteins, and many more. However, different proteins exhibit different structures which are adopted for various functions.

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