PowerPoint PresentationSlide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38Slide 39Slide 40Slide 41Slide 42Slide 43Slide 44Slide 45Slide 46Slide 47Slide 48Slide 49Slide 50Slide 51Slide 52Slide 53MCB 450Lecture 4Tertiary and Quaternary Structure of ProteinsGlobular ProteinsMotifs and DomainsFibrous ProteinsCollagenProtein BioinformaticsProtein Folding & DenaturationPost-translational Modifications of ProteinsAmyloidoses4-14-23-D folding of a polypeptide:i) simple combinations of 2° structuralelements = “motifs” or “folds”ii) combination of motifs/folds into “domains” Tertiary structureGlobular, fibrous, & membrane proteins• Globular: soluble and compactmany are cytoplasmicsome secreted from cells• Fibrous: insoluble, long strands or sheetsrepeating unit of 2° structure,many similar polypeptidestightly packed• Membrane: embedded in membranesmany have ≥ 1 -helical stretchesthat span a membrane4-33-D Structure of globular proteins• Conformation = spatial arrangement of atoms in a protein• Units of 2° structure (& connecting loops) arefolded into spherical or globular shapes• Units often made up of several types of 2° structure • Many different 3-D structures, many different functions, e.g. enzymes, regulatory proteins, DNA-binding....• Conformational changes possible(usually depend on binding of a ligand)• Hierarchical classification of protein structure:motifs (or folds) make up domains4-44-5• Motif/fold = stable arrangement of 2 or more elements of 2° structure+ the connection(s) between themhelix-loop-helixorhelix-turn-helix"EF-hand" motif in Ca2+-binding proteinse.g. in DNA-binding proteinsCommon structural motifs/folds in globular proteins motifhairpin- motifantiparallel -strandsActive site (= those involvedin catalysis)often in this loopparallel strands,separated by helix4-6 Common structural motifs/folds in globular proteinsMany arrangements of -strands are possible# of strands, their relative orientation, and how the strands are connectedalong the polypeptide chain (= strand order) vary, e.g.:No knots!Color coding here is justintended to help identifyeach -strand in 3D structure4-7Extended -sheets can roll up to form -barrels:4-8• Several motifs form a protein domain• Domain = fundamental unit of tertiary structure• One polypeptide chain can have several domains• Domains can have different functionsDomains4-9Constructing domains from motifs barrel consists of a seriesof loops arranged sothat the -strands form a barrel4-10motif/fold domain made up of motifsTwo proteins built from motifs4-11/ barrels in triosephosphate isomerase(8 parallel strands)Open twisted sheet found insome dehydrogenasese.g. in an enzyme with an barrel structure, the -strands and -helicesform the structural framework of the enzyme, and the active site isformed by loops at one end of the barrele.g. ribulose bisphosphate carboxylase(C5 + CO2 2 C3 in CO2 fixation)Charged sidechains in blue,substrate redLoops often contain responsible for catalytic activity4-12Troponin C:each domaincan individuallybind calcium4-13 Domains may have distinct functions,even when separatedNCRNA-bindingNuclear transportfactor-like domainp15-bindingdomainLeucine-rich repeatsNXF1 protein: involved in RNA export from nucleus3° structure of myoglobinSpace-filling model withall amino acid side chainshemeSide chains of hydrophobic in blue:most are in the interior of the myoglobinmolecule, giving a dense hydrophobic core,from which most H2O is excluded8 -helical segments(≥70% of myoglobin’s )4-14 What about the side chains?http://www.laas.fr/N2IS-EN/28-32225-Structural-oncology-.php4-15Protein conformation doesn't always stay the same:conformational changes possible, especially when a ligand binds"ON""OFF"Ras proteinFlips between an active & an inactive conformation ± GDP/GTP.Mutated to activeconformation in~25% of human cancersSIGNALS GROWTHLymphotactinAn extreme case:i) Chemokine form(3-strand -sheet &C-terminal helix)ii) Carbohydrate-binding(dimer of all -sheets)Many proteins have multiple polypeptide subunits...Multisubunit proteins may contain two or more identical polypeptides,or may include different polypeptides4° structure usually stabilized by weak non-covalent interactionsbetween exposed on the surfaces of the polypeptide subunits(= same forces that stabilize the tertiary structures of proteins)The 22 tetramer of human hemoglobinQuaternary structure4-16Fibrous proteins• Polypeptide chains organized in long strands or sheets• Fundamental structural unit is a simple repeating unitof 2° structure: many similar polypeptide chainsare packed tightly together to form elaboratesupramolecular complexes• Hydrophobic and insoluble: e.g. keratin, silk4-17left-handed, super-twisted2 -helices, oriented in parallelSurfaces where helices touch madeup of hydrophobic with R-groupsmeshed together in regular, inter-locking patternRich in Ala, Val,Leu, Ile, Met, PheStructure further stabilized by S-Scross-links between keratin polypeptides-keratin, a fibrous protein4-184-19Protein 3D structure: silk fibroin, a fibrous protein4-20Layers of antiparallel -sheets, rich in Ala & Gly, permitclose packing of -sheets with interlocking arrangementof R-groups, stabilized by H-bonding between all peptidelinkages in each -strand. http://www.nanowerk.com/spotlight/spotid=4523.phpCollagen: a unique triple helical structure Repeating Gly-X-Y- tripeptide in each strand forms a helix w. 3 per turn.X = Pro, Y = hydroxyPro (Hyp). Hyp at the right place is critical for collagen stabilityNO H-bonds in an individual collagen strand: each stand stabilized by steric repulsion between the pyrrolidine rings of Pro and Hyp4-21Collagen: a unique triple helical structure Three collagen helices are twisted around each other to form a superhelical cable….The triple helical cable is stabilized by H-bonds between peptide NH groups of Gly and C=O groups on on adjacent chains4-22Hydroxyproline is made from Pro by an enzyme ENZYMATIC CONVERSIONDEPENDS ON ASCORBATE(VITAMIN
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