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Protein Diversity
Biochem and medical genetics
| Question | Answer |
|---|---|
| Give examples of basic proteins and their functions | Extracellular matrix-Collagens, proteoglycans, elastin Required to make connective tissue, hold cells together and form muscles, veins, arteries and capillaries Cytoskeleton- Actin, tubulin, spectrin Dictate cell shape, motility and strength |
| Name the two distinct categories of fibrous proteins | Passive structural proteins e.g. collagen Active components e.g. enzymes |
| Structure of fibrous proteins | Contain specific repetitive amino acid sequences necessary for their 3D shape (repetitive primary structure) Individual long chains are crosslinked, interleaved and intertwined to withstand compression and protect cells |
| Name three distinct structural groups of fibrous proteins | Coiled coil alpha helices e.g. keratin and myosin Triple helix e.g. collagen Beta sheets e.g. amyloid fibres and silks |
| How are fibrous proteins formed | Formed of protofilaments or protofibrils that can assemble into specific higher order filaments. These are processed in the proto form and activated at their functional site. |
| What is dynamic formation of fibrous proteins | The proteins can change shape e.g. microtubules elongating to move the cell. This occurs via addition and removal of protofibrils. Microtubules ability to grow is positively correlated to availability of GTP which causes polymerisation when bound. |
| What is the structure of collagen | 3 polypeptide chains consisting of repetitive sequences of Gly-X-Y where X is usually proline and Y is usually hydroxyproline These twist to form a left handed twist helical structure. The three helixes then aggregate into a right handed triple helix |
| How is collagen synthesised | As long precursors (protocollagen) with globular extensions at each end. In the ER these are hydroxylated etc with the globular extensions cleaved to join the triple helix via interchain disulphide bonds on terminal proteins to align the three chains. |
| What is the mature form of collagen | Tropocollagen - multiple triple helixes polymerised together via crosslinks into a complex network This crosslinking occurs via post translational modification of lysine along with addition of other AA e.g. histidine |
| What role does water play in collagen stability | The extra OH on hydroxyproline allows large numbers of H bonds to be formed with water. This hydrates the structure and allows the extracellular matrix to act as a shock absorber |
| How are the globular extensions of collagen cleaved | When procollagen is secreted from fibroblast cells into the extracellular space specific peptidases cleave the amino and carboxyl termini to allow aggregation of tropocollagen |
| Explain how Osteogenesis imperfecta results from abnormal collagen | Genetic disorder resulting in brittle bones and bone deformities. Caused by short alpha helices within collagen that cannot form stable triple helixes or glycine replacement by cystine or arginine in the collagen repeat motif that has the same effect |
| Explain how Ehlers-Danlos Syndrome results from abnormal collagen | A group of disorders from weakened connective tissue characterised by hyperextensible skin and recurrent dislocations. Cased by reduced hydroxylated lysine residues, impaired formation of tropocollagen. This is associated with abnormal enzyme action |
| Structure of Keratin | A structural protein found in hair, nails etc that belongs to a family of intermediate filaments. This is characterised by Heptad repeats typical for coiled coil proteins. This is largely alpha helical with a pair of helices twisted to form a coiled coil. |
| How is mature keratin formed | Made of coiled coils joined in a staggered array bridged by disulphide bonds . These protofilaments assemble into protofibrils via globular domains This is rich in hydrophobic amino acids making the fibres stick together in aqueous environments |
| Examples of membrane transporters | P-glycoprotein MATE (multidrug and toxin extrusion protein) PepT1 Organic Anion/Cation transporter These are important for moving metabolites around the body and in drug resistance and adverse drug-drug reactions |
| P-glycoproteins | ABC transporters are responsible for removing toxic molecules from the cell. P-glycoprotein is coded for by the ABCB1 gene and is responsible for excreting xenobiotic compounds back into the gut. This can reduce effectiveness of anti-cancer therapies. |
| What do p-glycoproteins transport | Chemotherapeutic agents: etoposide, doxorubicin and vinblastine Lipids, steroids, peptides and bilirubin |
| ABC transport mechanism | The binding site is positively charged so negative ATP binds. This pulls the two sides together, causing a conformational change which opens the transporter. ATP is hydrolysed to ADP, which is less negative so cannot hold the protein together. |
| Structure of ABC transporters | Alpha helix to anchor in the membrane Globular domain to bind to ATP inside the cell |
| Roles of ABC transporters in eukaryotes | CFTR chloride ATP regulated channel SUR1- subunit of the inward-rectifier potassium ion channels, manipulates electrical conductivity of the membrane TAP1/2 responsible for loading peptides onto the MHCI molecules for immune presentation |
| What are kinases | A large superfamily of proteins that transfer the phosphate from ATP onto donor sites on proteins, lipids and carbohydrates |
| Example of a kinase- Hexokinase | Traps glucose in a cell and is the first step in glycolysis. Substrates of fructose, manose and xylose. The binding of ATP requires Mg2+. This is inhibited by its produce via negative feedback |
| Isoforms of hexokinase | Hexokinase I,II,III are low Km isozymes with a high affinity for glucose. These are found in all mammalian tissues and show Michaelis-Menton kinetics.# Hexokinase IV found in the liver has a lower affinity for glucose |
| How does Hexokinase work | Glucose binds to the sugar binding region causing a conformational shape. The movement of a lobe encloses the binding site to create optimal conditions This allows ATP to bind to the kinase domain. This is an example of an induce fit mechanism. |
| An enzyme with multiple domains- Pyruvate kinase | Catalyses the final step of glycolysis to produce pyruvate and ATP. This has a Beta saddle domain which encloses the active site to achieve catalysis. The TIM barrel domain allows for binding of the substrate. alpha helical regulatory Fructose bis-P site |
| Steroid receptors as regulatory proteins | Found in the nucleus, cytosol and on plasma membrane. Intracellular and bind to steroid hormones. This binding induces a conformational change to allow them to enter the nucleus and activate genes. Include NR3 subfamily for oestrogen receptor |
| Structure of steroid hormones | Variable domain DNA binding domain- globular motifs binding zinc to four cystines Hinge domain Hormone binding domain- when bound to a hormone induces a change in DNA binding region |
| Zinc Finger DNA binding domains | Comprises 30 amino acids with 2 cystines and 2 histamines which bind to zinc. The link between the last Cystine and first histidine is long and known as the finger region. These occurs in transcription factors with more present giving better specificity. |
| Do zinc fingers bind to specific regions | There is no specific correspondence between individual amino acid residues and which base it contacts, instead it is dependant on the order of amino acids in the four critical positions on the alpha helix. |
| Leucine Zippers as transcription factors | These are found in mammalian TF C/EBP and three oncogenes Fos, Jun and Myc. These form coiled coils which attract other molecules e.g. RNA polymerase whilst 2 helices come together to interact with DNA. |
| Immunoglobulins | Antibodies are produced by B cells and have a basic structure of two light and two heavy chains. They are Beta domains with 5 main isotypes: G,M,A,D,E with M being the main form in the body. Loop regions are the main functional area, so are very long |
| Variable region of an antibody | Each has an amino terminal variable domain Variable domains are not uniformly variable, but variation is localised to the hyper variable regions or complementarity determining regions which determine specificity. 9 strands in this region |
| Constant region of an antibody | Each has a carboxyl constant domain. These a made from seven beta strands arranged so 4 strands form one beta sheet and 3 strands form the second. A disulphide bridge cross links strand F to strand B. |
| What does Papain do | Cleaves IgGs into Fab (Fragment antibody binding) or the light chains and Fc (fragment that crystallises easily) or the heavy chains |
| Where are immunoglobulins found | Antibodies Cell membranes- binding, scaffolding, cell recognition |
| Insulin | A peptide hormione produces by beta cells in the pancreas which regulates uptake of glucose. Comprosed of 110 AA and is a dimer of an alpha and beta chain joined via disulphide bonds. |
| How is insulin synthesised | First synthesised as pre-proinsulin (single chain) then cleaved in the RER to pro insulin before conversion to insulin through action of prohormone convertases. Stored as a hexamer but converted to a monomer for action |
| How has insulin been modified for medical use | Glargine- Long acting as asn A21 >> gly + arg.arg which changes the charge to neutral so it is less soluble so acts slower Determir- Long acting as a fatty acid is attached to lys B29 to bind to albumin in blood Novorapid- rapid acting as Por B8 >> asp |
| Regulation of insulin production | Glucose enters cytoplasm via glucose transporter This is used to respiration to produce ATP ATP sensitive K channels close so K cannot exit cell Membrane depolarises and Ca moves in Vesicle containing insulin move to membrane |
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