Protein Structure and Functions Lecture 12 PDF

Lippincott’s illustrated reviews Chapter 2, Page 13 Lecture 12 protein Structure and Functions 1  Specific Objectives By the end of this lecture students can be able to: Explain the levels of the organization...

Lippincott’s illustrated reviews Chapter 2, Page 13 Lecture 12 protein Structure and Functions 1  Specific Objectives By the end of this lecture students can be able to: Explain the levels of the organization of proteins Know the characters of peptide bonds Differentiate between folding, unfolding and misfolding Discuss Amyloid and Alzheimer diseases 2  Proteins Proteins are the most abundant and functionally diverse molecules in living systems. Virtually every life process depends on this class of molecules. Proteins are formed of amino acid residues linked together by peptide bonds. 3  Protein have different levels of structural organization; primary, secondary, tertiary and quaternary structure. Alpha These structures required for its specific biological function or activity. 4  1. Primary structure of proteins: It is the sequence of amino acids in the polypeptide chain. Understanding the primary structure of proteins is important because many genetic diseases resulted in protein with abnormal amino acid sequences, which cause improper folding and loss or impairment of normal function. It helps in diagnose or study the disease. 5 6  A. Peptide pond In protein, amino acids are joined covalently by peptide bonds, which are amide linkages between the α-carboxyl group of one amino acid and the α-amino group of another. coNH bridge 7  Peptide bonds are not broken by conditions that denature proteins, such as heating or high concentrations of urea. Prolonged exposure to a strong acid or base at elevated temperatures is required to hydrolyze these bonds non-enzymatically. 8  B. Determination of the amino acid composition Determination of the primary structure of a polypeptide is to identify and quantitate its constituent amino acids. A purified sample of the polypeptide to be analyzed is first hydrolyzed by strong acid at 110°C for 24 hours. This treatment cleaves the peptide bonds and releases the individual amino acids, which can be separated by cation- exchange chromatography. 9 10  2. Secondary structure of proteins: Coiling, folding or bending of the polypeptide chain. There are two main regular forms of secondary structure; α-helix and β-pleated sheets. 11  α- Helix β- Pleated 1. It is rod like structure, coiled 1. It is Sheet like structure, polypeptide chain arranged in composed of two or more spiral structure peptide chain 2. All hydrogen bonding are 2. Interchain between separate insidE intrachain polypeptide chain and intrachain in a single polypeptide chain folding back on its self. side inside 3. The spiral of α-helix prevents the 3. The chain are almost fully chain form being fully extended extended and relatively flat. They directional may be parallel or anti parallel. by Eg. It is abundant in hemoglobin Eg. It is abundant in proteins like and myoglobin silk fibroin and carbonic anhydrase. 12 α-helix: 13 β-pleated sheet: 14 3. Tertiary structure of proteins: can be heli Tertiary refers to the folding of domains. orsheet ontogethe by 31 Domains are the fundamental functional and three- dimensional structural units of polypeptides. The core of domain is built from combinations of super secondary structure elements. 15  Interaction stabilizing tertiary structure The following four types of interactions cooperate in stabilizing the tertiary structures of globular proteins: 1. Disulfide bonds. A 2. Hydrophobic interactions. Depends 3. Hydrogen bonds. on amino I want 4. Ionic interactions. 16 4. Quaternary structure of proteins: Proteins possess quaternary structure if they consist of 2 or more polypeptide chains (monomer or subunit). Subunits are held together by noncovalent interaction (as hydrogen bonds, ionic bonds, hydrophobic interactions). 17 18 19  89 Protein folding 5 Protein folding, which occurs within the cell in seconds to minutes, employs a shortcut through the maze of all folding possibilities. As a peptide folds, its amino acid side chains are attracted and repulsed according to their chemical properties. For example, positively and negatively charged side chains attract each other, similarly charged side chains repel each other. 20 21  In addition, interactions involving hydrogen bonds, hydrophobic interactions, and disulfide bonds all exert an influence on the folding process. This process of trial and error tests many, but not all, possible configurations, seeking a compromise in which attractions outweigh repulsions. 22  Denaturation of proteins It is loss of the native structure and biological activity of the secondary, tertiary and quaternary structure of proteins when exposed to one of the denaturing agents. It is unfolding of the protein. I In this process the noncovalent bonds only break but the peptide pond did not break so primary structure is the only structure stable and did not alter by this process. Denaturing agents includes, Heat, Organic solvent, Strong acid or base, Detergent, Ions of heavy metals such as lead and mercury. 23  Protein misfolding Protein folding is a complex, trial-and-error process that can sometimes result in improperly folded molecules. These misfolded proteins are 2 usually tagged and degraded within the cell (quality control system). Deposits of the misfolded proteins are associated with a number of diseases 24  Amyloid disease Tiffawletdisolve Accumulation of the insoluble, spontaneously aggregating proteins, called amyloids to Causes: 1. Spontaneously. 2. By mutation in a particular gene, which then produces an altered protein. 3. After abnormal proteolytic cleavage in some apparently normal protein on a unique conformational state that leads to the formation of long, fibrillar protein assemblies consisting of β-pleated sheets. 25 26  Amyloids has been implicated in many degenerative diseases- particularly in the age-related neurodegenerative disorder, Alzheimer disease. Accumulation of beta The dominant component of the amyloid plaque that accumulates in Alzheimer disease is amyloid β (Aβ), a peptide containing 40-42 amino acid residues. 27  The aggregation of this peptide in a β-pleated sheet configuration, is neurotoxic, and is the central pathogenic event leading to the cognitive impairment characteristic of the disease. main symptom 28 Reference Book: Champe, P. C., Harvey, R. A. and Ferrier, D. R., 2005. Biochemistry “Lippincott’s Illustrated Reviews”, 5th or 6th Edition 29