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Lecture 9:Protein Architecture V:Evolution, Function &ClassificationMargaret A. DaughertyFall 2003BIOC 205DefinitionsBiochemical evolution: study of how proteins (and othermolecules) and biochemical pathways have changedthrough time.Homologous proteins: those derived from a commonancestor; share a significant degree of sequencesimilarityi). paralogs - homologs present within a species; ii). orthologs: -homologs that are present indifferent speciesDivergent evolution: Proteins derived from commonancestorsOrthologs vs. Paralogs35% sequence identity Sequence alignments: statistical survey of sequencesIn this examplewe are lookingat identicalmatches;Slide onesequence alongother and countup matchesInsertion of gaps helps alignments36 matchesConservative substitutions Replacing one amino acid by another similar in size & chargee.g., asp -> glu can you name other conservative changes?Rule of thumb: (assuming a 100 residue protein)>25% identity : homologous sequence <15% identity: probably not homologousParalogs: the oxygen binding heme proteinsBIOC 205Tertiary structure is more conserved than primary structurePHYLOGENETIC TREE FOR THE GLOBINSBIOC 205* gene duplication events play a major role here!****CONSERVATIONIN THE GLOBIN FOLDBIOC 205Sequence Alignment: Identification of homologous proteinscytochrome c: a favorite exampleYellow - invariant; blue - conservative; unshaded; non-conservedBIOC 205Comparison of sequence differences# of differences is proportional to the phylogenetic differenceBIOC 205Phylogenetic trees: evolutionary relatednessBIOC 205# of changes isproportional toevolutionary timesince the commonancestorHow human cyt c compares with its ancestral progenitorBIOC 205A). Tuna (5cyt)B). TunaC). Rice (1cc4)D). Yeast(1ycc)E). Bacterial (1hro)Conservation in structureBIOC 205Convergent evolution: different evolutionary paths lead tothe same solutionThe serine proteases: cleave peptide bonds by hydrolysisActive sites Protein structureGenetic VariabilityGene mutations (base substitutions) can lead to alteredamino acid substitutions; can be neutral, aberrant or non-functionalBIOC 205Hb S: Sickle cell HbHb S:A case studyBIOC 205High incidence of sickle cell allelegenerally coincides with highincidence of malaria;Heterozygotes have a higherresistance to malaria;The fragility of the RBCs tendsto interrupt the malarialparasites life cycle;Therefore, heterozygotes have ahigher survival rate & are morelikely to pass on their genes!• Sickle hemoglobin(HbS);• Mutation β6 E -> V;• Most common in peopleof African andCaribbean descent– 1 in 10-40 carry thetrait– 1 in 60-200 have thediseaseβ6 glutamic acid --> valine mutationStructural consequence of the mutationBIOC 205β6 glutamic acid --> valine mutationStructural consequence of the mutationClinical Manifestations• Due to their shape, sickled RBCscan't squeeze through smallblood vessels as easily as thealmost donut-shaped normalcells;• This can lead to these smallblood vessels getting blocked,which stops the oxygen fromgetting through to where it isneeded;• This in turn can lead to severepain and damage to organs.BIOC 205Classification: we’ve seen thisEnzymes - catalyze chemical reactionsRegulatory proteins - control physiological functionTransport proteins - move substances around/between cellsStorage proteins - provide a reservoir for a substanceMotor proteins - endow cells with capability of movementStructural proteins - create and maintain biological structureProtective proteins -active role in cell defense or protectionExotic proteins - have specialized adaptive functionsThe simplification: And all this with just 20 amino acidsand some post-translational modifications!The reality: many proteins contain other chemical groups BIOC 205Conjugated ProteinsNomenclature: the word "conjugated" is from the Latin,con = withjugum = yokeThus, the protein and non-protein moieties are yokedwith one another (like oxen) to work together.Apoprotein = the protein without its non-proteincomponent;Prosthetic group = the non-protein portion alone;what wecall the non-amino acid component if it is crucial tofunction or influences the conformation of the protein.Conjugated or holo- protein = the apoprotein + prostheticgroup.BIOC 205Classification ofconjugated proteinsGlycoproteinsLipoproteinsNucleoproteinsPhosphoproteinsMetalloproteinsHemoproteinsFlavoproteinsBIOC 205Examples of Prosthetic GroupsHemePhosphateCarbohydrate LipidStephen Everse © 2001BIOC 205MetalloproteinsMetals found as prosthetic groups of proteins include:Mg, Ca, V, Cr, Mn, Fe, Co, Cu, Zn and Mo.These metals can form coordination complexes. They acceptelectron pairs from atoms with unshared electron pairs. The electronpairs fill vacant orbitals of the metal ion, such as sp3d2 orbitals. Someof these metals can easily undergo oxidation-reduction,e.g.Fe(II) = Fe(III) + e-All are relatively small; note, no heavy metals (e.g., Pb, Hg) areincluded!Stephen Everse © 2001BIOC 205Roles for Bound Metals• The metal acts as a polydentate ligand, thereby stabilizing the three-dimensional structure of the protein.Example: The gamma domain of fibrinogen looses its structure if Ca2+ is removed & can no longer clot.• Metals frequently participate in oxidation-reduction. Sometimes boundmetals participate directly in biological oxidation-reduction reactions byaccepting or donating an electron (changing oxidation state).Example: Cytochromes• Holding the protein and some other molecule together (e.g., an enzymeand its substrate are ligands of the metal ion simultaneously).Example: DNA polymerases with Mg++ ligated by 2-3 conserved acidic AAs and the triphosphate tail of the dNTPBIOC 205Mg, Ca, V, Cr, Mn, Fe, Co, Cu, Zn and Mo. GlycoproteinsProteins with carbohydrate prosthetic groupsFunctions:• First, recognition. Carbohydrate prosthetic groups serve asantigenic sites (e.g., blood group antigens are carbohydrateprosthetic groups), intracellular sorting signals (mannose 6-phosphate bound to a newly synthesized protein sends it tothe lysosomes), proteins which have lost their terminal sialicacid(s) are cleared by the liver, etc.• Second, structural. Structural components of the organism:e.g., the proteoglycans of cartilage.Stephen Everse © 2001BIOC 205GlycosylationTypical structure -- one or more chains of monosaccharide units, 1 to30 units long. It may be straight or branched, and it is usuallycovalently linked to the apo-protein in one of two major


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UVM BIOC 205 - Lecture Notes

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