Protein structure, levels of protein structure,.pptx

Protein Structure, Levles of protein structure, Domains, Motifs & fold in Protein structure

1. Presented by : Dhanaraj konapure M pharma 2 nd sem Guidence by : Miss Arati malpani Associate proffesor Department of pharmacology Protein structure, levels of protein structure, Domains, Motifs &folds in protein structure

2. Contents : Introduction Amino acids as fundamental units of protein. Primary level. Secondary level. Tertiary level. Quaternary . Domains Motifs Folds .

3. introduction Proteins are an important class of biological macromolecules which are the polymers of amino acids. Amino acids are the small organic molecules mainly containing amino group and carboxylic acid group. Amino acids are containing α carbon atom linked to an amino group , a carboxyl group, a hydrogen atom, and a variable component called a side chain. Within a protein, multiple amino acids are linked together by peptide bonds(amide bonds between the –NH 2 of one amino acid and the –COOH of another.), thereby forming a long chain. proteins are built from a set of only twenty amino acids . Each of which has a unique side chain.

4. Levels of protein structure: Biochemists have distinguished several levels of structural organization of protein. They are Primary structure Secondary structure Tertiary structure Quaternary structure

5. 1. Primary structure of proteins : It is the first level of protein structure –linear structure which is the sequence of amino acids that make up a protein. These amino acid sequence of protein is encoded in DNA. Amino acids are covalently linked by peptide bonds. Each component amino acid in a polypeptide is called a “residue” or “moiety” A change in the gene’s sequence may lead to a change in the amino acid sequence of the protein. A change in one amino acid in a protein’s sequence can effect the protein’s overall structure and function.

6. Importance of primary structure To predict 2 and 3 structures from sequence homologies with related proteins. many genetic diseases result from abnormal amino acid sequences. To understand the molecular mechanism of action of proteins. To trace evolutionary paths.

7. 2 . Secondary structure : The structure of a protein –it’s amino acid sequence –drives the folding and intramolecular bonding of the linear amino acid chain, which ultimately determines the protein’s unique three-dimensional shape. Hydrogen bonding between amino groups and corboxyl groups in neighboring regions of the protein chain sometimes causes certain patterns of folding to occur. Linus pauling proposed some essential features of peptide units and polypeptide backbone. They are The amide group is rigid and planar as a result of resonance. So rotation about C-N is not feasible. Rotation can take place only about N-C α and C α -C bonds. Trans-configuration is more stable than cis -for R groups at C α

8. From these conclusions pauling postulated 2orderd structure: α helix and Β sheet These stable folding patterns make up the secondary structure of protein.

9. ALPHA HELIX: Spiral structure. Tightly packed, coiled polypeptide backbone core. Side chain extend outwards Stabilized by H bonding b/w carbonyl oxygen and amide hydrogen. Amino acids per turn-3.6 Pitch is 5.4 A Alpha helical segments are found in many globular proteins like myoglobins , tropornin -C etc.

10. BETA PLEATED SHEET: Formed when 2 or more polypeptides line up side by side . Individual polypeptide – β stand Each β stand is fully extended. They are stabilized by H bond b/w N-H and carbonyl groups of adjacent chains. Beta pleated sheet are two types Parallel Anti-parallel N C N C N C N C

11. β sheet structure

12. 3. Tertiary structure : Tertiary structure is the three dimensional conformation of a polypeptide. Its is formed spontaneously and stabilized both by side chain interactions and, in extracellular proteins ,by disulfide bonds. This folding brings distant sequences in a linear polypeptide together into a stable structure. Tertiary conformation takes place such that hydrophobic in the interior side and hydrophilic on the exterior side The common features of protein tertiary structure reveal much about the biological functions of the proteins and their evolutionary origins. The function of a protein depends on its tertiary structure. If this is disrupted it loses its activity.

13. Based upon their tertiary structure, proteins are often divided into Fibrous types - Fibrous proteins, like α-keratin, have elongated rope-like structures that are strong and hydrophobic proteins, having polypeptide chains arranged in long strands or sheets. Globular types - Globular proteins, like the plasma proteins and the immunoglobulin's, are more spherical and hydrophilic. The two groups are structurally distinct: fibrous proteins usually consist largely of a single type of secondary structure; globular proteins often contain several types of secondary structure. Both primary and secondary structure involves main chain atoms but here in tertiary we see involvement of side atom of AA Globular protein- highly folded and compact Fibrous- long and spindly Fibrous— keratin,collagen,myosin

14. Tertiary structure formed by interaction between R group Hydrophobic interactions: Hydrophobic side chains are repelled by water and forced together at the interior of proteins to escape the aqueous environment. Vander Waals forces: A nonspecific attraction develops based on the proximity of interacting atoms; if the shape of the side chain allows a good fit between surfaces, an attractive force develops. A poor fit gives either repulsion or no force. Electrostatic bonds: Oppositely charged side chains can attract each other, forming salt bridges. They also play a role in the binding of substrates and allosteric effectors and in the association of the protein with other protein molecules (i.e., in Quaternary Structure). In addition, they can bind large amounts of water to solubilise the protein when located on the surface.

15. Hydrogen bonds: Polar groups can share a partial positive charge between a hydrogen donor and a hydrogen acceptor to form a weak bond. Disulfide bonds: Sulphur containing amino acids like cysteine and methionine interact with each other and form a strong covalent bond called disulfide bridge or disulphide bond

16. 4.Quaternary structure: Many proteins are made up of multiple polypeptide chains, often referred to as protein subunits is called quaternary structure or the quaternary structure of a protein is the association of several protein chains or subunits into closely packed arrangements. These subunits may be the same (as in a homodimer ) or different (as in a heterodimer ). Each subunit has its own primary, secondary and tertiary structure. The quaternary structure refers to how these protein subunits interact with each other and arrange themselves to form a larger aggregate protein complex.

17. The final shape of the protein complex is once again stabilized by various interactions, including hydrogen-bonding, vander waals forces between no polar side chains and other than that there are also disulfide bridges and salt bridges. The subunits must be arranged specifically for entire protein to function properly Any alteration in the structure of subunits or how they are associated causes marked change in their biological activity

18. A. Domains A protein domain is a conserved part of a given protein sequence and (tertiary) structure that can evolve , function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. A domain usually contains between 40 and 350 amino acids, and it is the modular unit from which many larger proteins are constructed. The different domains of a protein are often associated with different functions. Eg . the Src protein kinase , which functions in signalling pathways inside vertebrate cells. This protein has four domains: the SH2 and SH3 domains have regulatory roles, while the two remaining domains are responsible for the kinase catalytic activity. They explain how proteins can form molecular switches that transmit information throughout cells. The central core of a domain can be constructed from α helices, from β sheets, or from various combinations of these two fundamental folding elements. Each different combination is known as a protein fold.

19. B. Motifs Protein motifs re small, discrete, commonly observed aggregates of secondary structure  These are small regions of protein three-dimensional structure or amino acid sequence shared among different proteins. They are recognizable regions of protein structure that may (or may not) be defined by a unique chemical or biological function. A motif is a recognizable folding pattern involving two or more elements of secondary structure and the connection(s) between them. Or “The connectivity between secondary structure elements and the type of secondary structure elements involved define the level of structural organization called structural motifs”. A motif is simply a folding pattern. Motifs do not allow us to predict the biological functions: they are found in proteins and enzymes with dissimilar functions. In proteins, a structural motif describes the connectivity between secondary structural elements.

20. Types of motifs: A motif can be very simple, such as two elements of secondary structure folded against each other, and represent only a small part of a protein. An example is a β-α-β loop . A motif can also be a very complex structure involving scores of protein segments folded together, such as the β barrel. Motif mediated protein-protein interactions as drug targets: In addition, numerous oncogenic proteins either contain a motif, or recognise motif interaction sequences for which inhibition is a potential cancer treatment . It has also been recognized that several viruses, e.g., Ebola and Rabies viruses, hijack the cell machinery using modified domain motifs interactions. For instance, Liddle’s , Noonan’s and Usher’s hereditary syndromes can be caused by mutations in the recognition motif (PDZ recognition motif respectively) leading to the deregulation of important signalling pathways. There are several diseases and syndromes related to the disruption of specific DMI (drug mediated interaction) motifs.

21. C. Protein folds As the polypeptide chain is being synthesized by ribosome, the linear chain begins to fold into its three-dimensional structure by molecular chaperones . Molecular chaperones are a class of proteins that aid in the correct folding of other proteins. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil. Each protein exists as an unfolded polypeptide or random coil when translated from a sequence of mRNA to a linear chain of amino acids. This polypeptide lacks any stable (long-lasting) three-dimensional structure. As the polypeptide chain is being synthesized by a ribosome, the linear chain begins to fold into its three-dimensional structure by molecular chaperones. Folding begins to occur even during translation of the polypeptide chain. Amino acids interact with each other to produce a well-defined three-dimensional structure, the folded protein, known as the native state.

22. Role of folds in different disease pathology: At least eight neurodegenerative disorders are caused by an expanded polyglutamine tract in the various disease proteins, including Huntington’s disease and spinocerebellar ataxia type 3. Polyglutamine expansion causes the disease protein to misfold and aggregate, ultimately leading to neuronal death Variants of the serpin ( superfamily of proteins), antitrypsin, misfold and accumulate in the endoplasmic reticulum of hepatocyte cells, leading to a plasma deficiency and hepatocyte damage due to the accumulation of aggregated protein, leading to cirrhosis and emphysema. We study two protein families involved in misfolding disorders: the serine proteinase inhibitor ( serpin ) and polyglutamine family of proteins. Most proteins have no trouble folding quickly and efficiently to their native state. However, an increasing number of diseases such as emphysema, Alzheimer’s and Huntington’s disease are associated with the failure of proteins to fold correctly. A protein fold   refers to a general aspect of protein architecture, like helix bundle, beta- barrel,  Rossman fold   or other "folds

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