Protein Chemistry 2 Lecture Notes PDF

Field of Medicine Medicine And Surgery Program Lecture : Protein chemistry 2 Dr : Moataz maher Date : 10 /2024 Objectives: By the end of this lecture the student will be able to: 1. Describe the four levels of protein organization. 2. Identify covalent and non-covalent bonds resp...

Field of Medicine Medicine And Surgery Program Lecture : Protein chemistry 2 Dr : Moataz maher Date : 10 /2024 Objectives: By the end of this lecture the student will be able to: 1. Describe the four levels of protein organization. 2. Identify covalent and non-covalent bonds responsible for protein conformation. 3. Recognize the concept of protein denaturation 4. Identify the role of chaperones in protein folding and diseases associated with abnormal folding. Four Levels of Protein Structure  Protein Structure 1ry Structure: Describes 1) the number and type of amino acids that form the polypeptide and 2) the sequence of amino acids linked together by peptide bonds. Met-Gly-Ala-Pro-His-Ile-Asp-Glu-Met-Ser-Thr-……. 2ry Structure: Describes the process of coiling of the formed polypeptide. This structure is stabilized mainly by H-bonding between amino acid residues.  Protein Structure 3ry Structure: It is the twisting of the coiled or uncoiled polypeptide chains. It represents the overall three-dimensional conformation of a protein. 4ry Structure: It is the association of more than one polypeptide into a protein complex. 7 Protein Structure (Forces stabilizing structure) 1. Electrostatic/ionic 2. Hydrogen bonds 3. Hydrophobic interactions 4. Disulfide bonds  Protein Structure (Forces stabilizing structure) 1. Disulfide bonds They occur between 2 cysteine residues in the same polypeptide chain or in different polypeptide chains  Protein Structure (Forces stabilizing structure) 2. Hydrogen bonds: Amino acid side chains containing oxygen- or nitrogen-bound hydrogen can form H-bonds with electron-rich atoms such as the oxygen of a COOH group or carbonyl group (C=O) of a peptide bond.  Protein Structure (Forces stabilizing structure) 3. Hydrophobic interactions: - When exposed to water, the non-polar side chains of amino acids tend to be located in the interior of the polypeptide molecule to associate with other hydrophobic amino acids. - Amino acids with polar or charged side chains tend to be located on the surface of the molecule in contact with the polar solvent.  Protein Structure (Forces stabilizing structure) 4. Electrostatic interactions (ionic bonds) – Negatively charged groups, such as the COO- in the side chain of amino acid (not the one in peptide bond) can interact with positively charged groups, such as the – NH3+ in the side chain of another amino acid. NH3+ of basic amino acids and the COO- of acidic amino acids.  Protein Structure (Secondary structure) The peptide backbone has areas of positive charge and negative charge These areas can interact with one another to form hydrogen bonds The result of these hydrogen bonds are two types of structures: - α-helices - β- pleated sheets H-Bond 1 6 Protein Structure (Tertiary structure) - It refers to the three dimensional conformation of a polypeptide. - It indicates, how secondary structural features— helices, sheets, bends, turns, and loops—assemble to form domains and how these domains relate to one another. - A domain is a section of protein structure sufficient to perform a particular chemical or physical task. e.g. binding of a substrate  Protein Structure (Quaternary structure) - Many proteins consist of a single polypeptide chain, and are defined as monomeric proteins. Others may consist of two or more polypeptide chains that may be structurally identical or totally unrelated [multimeric protein]. The arrangement of these polypeptide subunits is called the quaternary structure of the protein. - Subunits are held together by noncovalent interactions (H-bonds, ionic bonds, and hydrophobic interactions). - Proteins can be homo-multimers or hetero-multimers. -Homomultimer- several chains from same kind of chain -Heteromultimer-two or more different chains  Protein Denaturation Denaturation is the loss of the structural order (secondry, tertiary and quaternary) which are not accompanied by hydrolysis of peptide bonds, this leads to loss of the protein biological activity. ✓ Denaturing agents include: heat, organic solvents, mechanical mixing, strong acids or bases, detergents, and ions of heavy metals such as lead and mercury. They can disrupt hydrophobic interactions, hydrogen bonding or reduce disulfide bonds ✓ Most proteins, once denatured, remain permanently disordered. ✓ Denatured proteins are often insoluble and, therefore, precipitate in solution.  Protein Folding/Misfolding ✓ Folding of the protein into its 3D conformation is essential for its function. Only a single form results into a functional protein. ✓ The amino acid sequence of proteins determines the overall folding. Any mutation in one or more amino acids will result in abnormal folding with subsequent dysfunction of the protein. ✓ A group of proteins known as chaperones are required for the proper folding of proteins.  Protein Folding/Misfolding The chaperones—also known as “heat shock” proteins—interact with the polypeptide during the folding process to help in the following: 1) They bind reversibly to unfolded polypeptide segments and prevent their misfolding until their synthesis is finished. Or 2) They protect proteins as they fold so that their exposed regions do not share in wrong interactions. Or 3) They assist in destruction of a protein that can not be folded into its proper conformation.  Protein Folding/Misfolding Improper protein folding (misfolding) are tagged and degraded within the cell. Failure of correction of misfolding results in aggregates of misfolded proteins intracellularly or extracellularly. The protein deposits are called amyloid and the disease is known as amyloidosis. Disease associated with protein misfolding: 1. Alzheimer disease [progressive decline in memory cognition and behavioral stability]:It is the Most Common Neurodegenerative Disorder Some proteins can undergo misfolding spontaneously, or due to gene mutation, and that leads to the formation of neurotoxic amyloid protein, amyloid β(Aβ).It consists of β-pleated sheets that aggregates in neurons. This aggregate disrupt cell to cell communication and activate immune cells. This immune cells causes inflammation.  Protein Folding/Misfolding 2. Prion disease: Prion protein (PrP) has been implicated as the causative agent of transmissible spongiform encephalopathies (TSEs) such as mad cow disease. The protein (PrP) is highly resistant to proteolytic degradation, and tends to form insoluble aggregates similar to the amyloid found in other diseases of the brain.  Protein Folding/Misfolding 3. Cystic fibrosis: Cystic fibrosis is a genetic disorder that impairs the normal clearance of mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria that causes severe damage to the lungs. Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. Mutations of the cystic fibrosis transmembrane conductance regulator(CFTR) gene lead to misfolding and dysfunction of the CFTR protein. The faulty CFTR protein affects how minerals and water move in and out of cells.  Protein Folding/Misfolding 4. Parkinson's disease (PD): The second most common neurodegenerative disorder, involves the misfolding of a protein named alpha-synuclein (α-syn), whose aggregation generates Lewy bodies (LBs) that can be found in neurons and causes nerve cells death. Usual symptoms include tremors, slowness of movement, rigidity,shuffling gait, mask face and difficulty with balance.  Protein Folding/Misfolding 5. Huntington's disease (HD)also known as Huntington's chorea: is an incurable neurodegenerative disease that is mostly inherited.The earliest symptoms are problems with mood or mental/psychiatric abilities. General lack of coordination, an unsteady gait and hyperkinetic movement disorder known as chorea. It is due to mutation in the huntingtin gene provides the genetic information for huntingtin protein (Htt). Expansion of CAG repeats of cytosine-adenine-guanine (known as a trinucleotide repeat expansion) in the gene coding for the huntingtin protein results in an abnormal mutant protein (mHtt), which gradually damages brain cells.  Proteins are organized into 4 levels (primary, secondary, tertiary, quaternary) Proteins structure are maintained by different covalent and noncovalent bonds Protein misfolding is corrected by specific sets of proteins known as chaperones  Protein structure and folding link: https://www.youtube.com/watch?v=1peFJ_-N7V8 Reference: – Lippincott's Illustrated Reviews: Biochemistry, 7th Edition. Chapter 2. Best wishes