Main Ideas - Different aa's fulfill diff. functions w/regard to protein folding"- Protein folding is determined by covalent bonds and noncovalent forces (ionic interactions, hydrogen bonding, van de waals, hydrophobic interactions)"- There are 4 levels of protein organization"- There are several secondary protein structure types"- Refolding of a protein can result in cross-beta filament formation-->protein aggregation (amyloids)"- Amyloid diseases are typically associated w/neurodegenerative diseases and aging ""Learning Objectives 1) Understand the diff. chemical properties of aa's 2) Identify the major functional groups (R-groups) on proteins and understand their chemical properties 3) Know the non-covalent forces that drive protein folding 4) Know the 4 diff. levels of protein organization and the diff. secondary structural elements 5) Understand the basic idea of amyloid diseases and the examples mentioned 1) Understand the diff. chemical properties of aa's - Proteins are made of aa's"- Free aa's = zwitterions= contain both + and - groups"- They are ionized in sol'n (pH 7) to NH3+ and COO-"- NH2= amino group, COOH= carboyxl group, -X= side chain"- At low pH: carboxyl group is protonated and amino group is protonated"- As you go up in pH: carboyxl groups start to get deprotonated"- At higher pH: the amino group starts to get deprotonated "- The aa's that have additional chargable side chains--> more complicated"- Note: pK, half and half between structure before and after the dividing line"- Protein components"- Amino terminus= N terminues (NH3+)"- Polypeptide backbone (how its all linked together)"- Peptide bonds= link aa's together, form between C term of one aa (on left) and N term of another aa (on right)--> thus the charges there disappear, so only the side chains stay relevant"- Carboxyl terminus = C terminus (COO-) 2) Identify the major functional groups (R-groups) on proteins and understand their chemical properties - Nonpolar hydrophobic "= not soluble in water, hydrophobic components will always try to be on the side of the aa""""""""- Polar, Negatively charged - Polar, Positively charged - Polar, Neutral"- Don't have an overally + or - charge, they're polar because they can H bond-->highly soluble in water"- Circled OHs= targets for protein phosphorylation""""""" 3) Know the non-covalent forces that drive protein folding - Imp for protein folding-->aa's with chargaeable side chains"- Going from low to high pH"- and + charges contribute to protein folding"- Note: histidine isn't a huge contrib. to protein folding because it's half and half at physio pH"- Steric limitations on bond angles"- Non-covalent forces"- Electrostatic interactions - Occur between opp. charged residues"- Sidechain--Sidechain: Asp (-) and Glu (-) LOVE Lys (+) and Arg (+)"- Can involve the N and C termini of a protein"- May inv. post-translational mods"- Note: not all charged aa's will ion pairs w/others-->those that are on the protein surface will be hydrated by water - Hydrogen bonding - Formed between an atom w/slight - charge and one with a slight + charge - van der Waals attractions - due to attraction of the e- cloud of one atom to the nucleus of a neighboring atom"- there's a minimum distance because the clouds also repel each other"- very weak (<H bonds)"- Hydrophobic interactions"- nonpolar aa's always try to stay on the inside, away from the water/outside aqeous envi4) Know the 4 diff. levels of protein organization and the diff. secondary structural elements - Primary structure: aa sequence - Secondary structure: e.g. alpha helix, beta sheet"- alpha helix: mediated by H bonding between the 1st aa's O and the 4th aa's N, next one between 4 and 8, so it's between every 44 aa's to stabilize the alpha helix, side chains aren't relevant"- the alpha helices can wrap around each other to form a coiled-coil (w/hydrophobic aa's on inside, touching each other)"- beta sheet: stabilized by H bonds, but very diff. functions and interactions than alpha helix"- can go both ways: parallel and anti-parallel"- Random coils and turns -->often connectors between alpha helices and B sheets - Tertiary structure: 3D organization of a polypeptide"- folding"- diff. subcomponents of a protein can have diff. tertiary structure"- one protein often has several domains"- domains are often assoc. w/diff. functions of the same protein (ex. 1 has catalytic activity)"- Each of these domains can have its own structure"- Ex. one domain has the activtiy, but all have to be together to make it work - Quaternary structure: complex of several polypep. chains"- proteins can have more than one polypep. chain--> quaternary structure"- can be made via: covalent bonds (ex. disulfide), but most interactions are due to the non-cov. forces above"- ex. homotetramer (4 identical subunits, but each made individually) or heterotetramer (not all 4 subunits are identical)"- ex. some proteins form long helical filaments-->actin filament"- Protein evolution - many domains have identical folds despite low seq. identity (convergent evolution)"- some proteins are seq.-related and have similar 3D folds (divergent evolution)"- individ. domains are remixed during evolution (exon shuffling) to give novel proteins w/new functions"- Covalent crosslinkages stabilize protein structure"- often used to help extracellular proteins to maintain structure"- can happen w/in one protein or between diff. proteins"- only contributes to tertiary and quaternary structure, aren't part of helping the a helix or B sheet assemble 5) Understand the basic idea of amyloid diseases and the examples mentioned - Abnormally folded proteins can aggregate"- caused by a protein that naturally exists in your body (has normal folds and structure) -->undergoes a rare conformational charge (into something flat, B sheet like)--> they can seed other proteins --> turns them into identical versions of themselves --> stacks of B sheets that completely insoluble --> grows and grows into these amyloid structure --> interupt things in thebody "- cross-beta filement = resistant to proteolysis"- produces distinctly staining deposits= amyloids - amyloid diseases - sometimes disease caused by the deposit and sometimes the deposits only correlate w/the disease"- most amyloid deposits are protein-based"- main cause for insolubility= large B sheet stack structure - soluble natural before counterpart often has a completely diff. secondary strcutre"- many ad's are assoc.
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