Protein Structures Lecture PDF

Secondary, Tertiary and Quaternary Protein structures Learning Outcomes Describe the different structural shapes of proteins Describe the different types of bonding and interaction which hold the proteins in their 3D shapes Describe different examples of secondary and tertiary pro...

Secondary, Tertiary and Quaternary Protein structures Learning Outcomes Describe the different structural shapes of proteins Describe the different types of bonding and interaction which hold the proteins in their 3D shapes Describe different examples of secondary and tertiary proteins Explain how a change in protein shape can contribute to a disease state Primary structure of proteins Sequence of amino acids present in a polypeptide chain Consists of A main backbone Distinctive side chains Held together by peptide bonds Typically 50-300 amino acids in length Titin consists of 27,000 Each component is called a “residue” or “moiety” Structure starts from the amino terminal (N) and ends in the carboxyl-terminal (C) end What is a protein? Chain of amino acids joined by peptide bonds in a specific sequence Not linear structure They are folded into compact shapes:- Coils Zigzags Turns Loops Conformations (3D shapes) of proteins have been determined for the last 50 years Spatial arrangement of atoms that depends on the rotation of bonds Can change without breaking of covalent bonds Under physiological conditions most proteins fold into a single stable shape – Native form Biological function depends on it Folding Creates three-dimensional structures Secondary Tertiary Quarternary Specific biochemical functions Forces responsible for these structures are primarily non- covalent Hydrogen bonding Di-sulphide bonds Secondary protein structure Structure results from pattern of hydrogen bonds Regular intervals along the polypeptide backbone Form between NH and CO groups Nitrogen – hydrogen bond donor Oxygen – hydrogen bond acceptor 2 typical shapes can occur Alpha helix (coils) Beta pleated sheets (folds) Alpha helix Coiled structure Main-chain CO and NH groups are hydrogen boned Every 4th residue ahead in the sequence Coil occurs after every 3.6 residues – referred to as pitch of the alpha helix Most alpha helixes are right-handed (clockwise) More energetically favourable Side chains of the amino acids point outwards Not involved in hydrogen bonding Proline Helix breaker as it does not have a H atom to be donated and the ring structure does not allow for rotation  Beta sheets “Pleated” sheets Composed of two (or more) polypeptide chains Termed: Beta- strands Strands are fully extended Strands linked to one another through hydrogen bonds Carbonyl oxygens to amide hydrogens on adjacent strands Can be parallel or anti-parallel Parallel sheets not as stable as anti-parallel sheets Short hand….. Secondary structures also have…. Structures of non-repeating 3D structures Characterised as turns or loops Cause changes in the polypeptide backbone Connect alpha helices and beta strands Loops often contain hydrophilic residues Turns – have 4 to 5 residues Most common reverse turns (beta Motifs Super-secondary structures Recognisable combinations of alpha helices, beta strands and loops which appear in a number of different proteins Some associated with a particular function Although structurally similar motifs may have different functions in different proteins Simplest example – helix-loop-helix found in calcium binding site Fibrous proteins Mainly for structural support Contain polypeptides that bind together to form long fibres or sheets. Are physically tough Insoluble in water Examples of α-keratin Collagen Silk fibroin  Alpha keratin Two right-handed alpha helices Intertwined to form a left-handed superhelix Coiled-coiled motif Rich in hydrophobic amino acids: Ala, Val, Leu, Ile, Met, Phe Very strong Disulphide bonds and hair styling Disulphide bonds and hair styling  Silk Fibroin Silk produced by silk worms, spiders etc Antiparallel β – sheets rich in Ala and Gly Will not stretch – sheets fully extended Is flexible because of intermolecular interactions Collagen Most abundant mammalian protein Unique secondary structure Glycine appears every third residues Three helical polypeptides form a coiled coil Chilean blob mystery Washed up on a beach in Chile Giant octopus??? Consisted of collagen fibres resistant to degradation Genetic analysis – Sperm whale!” Tertiary protein structure Completely folded and compacted polypeptide chain Many consist of several distinct globular units linked by short stretches of amino acid residues Units are called domains Can be a combination of different motifs Stabilised by interactions of amino acid side chains in non-neighbouring regions of the polypeptide chain Primarily non-covalent interactions Brings distant portions of the primary and secondary structures close together Residues Polypeptide chains may be extensive Exposed regions referred to as residues Residues can have unique functions Example: G protein-coupled receptors AKA Metabotropic receptors or 7 transmembrane receptors Single 400 – 500 polypeptide chains Coupled to intracellular effector systems Via G proteins Largest family of receptors 865 are currently known Most common single target of therapeutic action Protein folding and stability Extremely rapid chain reactions to form native conformation Depends on several non-covalent forces including:- Hydrophobic effect Hydrogen bonding van der Waals interactions Charge – charge interactions Weak individually but collectively account for the stability of the native conformation Weakness gives the flexibility to undergo small conformational changes Hydrophobic effect Proteins more stable in water when their hydrophobic side chains are aggregated in the protein interior rather than exposed on the surface Side chains forced to interact causing the polypeptide chain to collapse Creates a more compact molten globule Van der Waals and charge-charge interactions Van der Waals interactions Charge – charge Occurs between non-polar interactions side chains Form between oppositely Contribution to stability of charged side chains protein structure difficult Small contribution to the to determine stability of proteins Myoglobin - Structure Polypeptide chain of 153 amino acids Has 8 alpha helical regions – stabilised by hydrogen bonding Oxygen binding protein Extremely compact Interior is almost entirely non- polar Myoglobin – amino acid distribution Hydrophobic in yellow Charged amino acids in blue Protein folding is determined by hydrophobic effect Polypeptide chain folds to “protect” hydrophobic regions Quaternary protein structures Some proteins fall into this category Classed as the association of two or more polypeptide chains into a multi-subunit (oligomeric) protein Polypeptide chains may be identical or different Protein denaturation The shape of proteins is key to function If connections are altered the proteins may become dysfunctional Contribute to disease states Disruption of Neuronal Action in Alzheimer's Disease Amyloid plaque Neurofibrillary formation Tangles Aberrant cleavage of the β amyloid Tau protein filaments precursor protein results in oligomers. control neuronal microtubule Extracellular aggregation are organisation. neurotoxic and may disrupt neural Hyperphosphorylation of connections. the tau protein prevents the formation of organised microtubules leading to axonal atrophy due to loss of structural integrity. Unboun d Peptid Oligomer Plaque e s Normal microtubule Synaptic plasticity. Impairment of organisation. Neurogenesis. neuronal function. Anti-oxidant. Neuronal cell death. Hyperphosphorylated tangle. Summary There are 4 known classes of protein structure Primary – polypeptide chain of amino acids Secondary – chains of amino acids held together by hydrogen bonding between NH and CO groups Form distinct structures including alpha helices, beta sheets and loops or turns Links can occur between these different secondary structures called motifs Examples of secondary protein structures include alpha keratin and collagen Tertiary – further folding occurs condensing the structure of the proteins Hydrophobic regions protected in the middle Stabilised by van der Waals interactions and charge-charge interactions