6-Protein structure

• Proteins undergo folding to follow the desired conformational state encoded in its amino acid sequence
• Proper folding is necessary for the protein to carry out its physiologic function
• Misfolding leads to the production of unusable proteins, causing debilitating diseases like amyloidosis
• The biologically active form of a protein is a three-dimensional molecule
• The 3D structure consists of primary, secondary, tertiary, and quaternary structure
• Protein molecule is held together by covalent and non-covalent bonds
• Covalent bonds in a protein molecule
• Peptide bonds link several amino acids together in polypeptide chains
• Disulfide bonds form between and within polypeptide chains
• Amide bonds are created between carboxyl or amine side chains
• Non-covalent bonds in a protein molecule
• Include hydrogen bonds, hydrophobic interactions, and ionic bonds
• These bonds help stabilize the 3D structure of the protein
• Primary structure is defined by the sequence of amino acids held together by peptide bonds
• Amide bonds and disulfide linkages also link amino acids together
• Amide bonds are created between AA side chains containing carboxyl or amine groups
• Disulfide linkages occur between two cysteine residues, forming cystine
• Secondary structure refers to regular arrangements in space of adjacent amino acid residues in a polypeptide chain
• Maintained by hydrogen bonds between amide hydrogens and carbonyl oxygens
• Major secondary structures are α-helices, ß-pleated sheets, and ß-bends
• Tertiary structure is the overall three-dimensional arrangement of the polypeptide chain in space
• Stabilized by outside polar hydrophilic hydrogen and ionic bond interactions
• Internal hydrophobic interactions occur between nonpolar amino acid side chains
• Folding is guided by chaperones, proteins that prevent premature aggregation
• Proteins are grouped based on their tertiary structure
• Fibrous proteins have elongated rope-like structures and are hydrophobic (e.g., α-keratin)
• Globular proteins are spherical and hydrophilic (e.g., plasma proteins, globulins)
• Quaternary structure is exhibited by proteins with more than one polypeptide chain
• Hemoglobin combines two α-chains and two ß-chains with four heme groups
• Enzymes can be combined into quaternary structures to act sequentially on substrates
• Prion diseases involve inappropriate conformations of brain proteins
• Can be genetic, infectious, or sporadic
• Involve modification of the secondary-tertiary structure of the prion protein (PrP)
• Examples include scrapie in sheep and Bovine Spongiform Encephalopathy (Mad Cow Disease) in cows
• Protein denaturation causes the loss of biological activity of proteins
• Causes include extreme temperature and pH, detergents, or substances that reduce disulfide bonds
• Protein renaturation is almost always impossible, making denaturation irreversible and terminal
• Exception: when the primary structure becomes intact, renaturation may be possible