Protein Architecture V: Evolution, Function & Classification. Lecture 9: Amino acid use units. Caveat: collagen is a. Margaret A. Daugherty.

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1 Lecture 9: Protein Architecture V: Evolution, Function & Classification Margaret A. Daugherty Fall 2004 Amino acid use *Proteins don t use aa s equally; eg, most proteins not repeating units. Caveat: collagen is a repeat of Gly-X~Pro *Most used once; Caveat: exceptions exist! *Composition can reflect function; histones bind DNA and are rich in R and K ADH is representative of Soluble (globular) proteins

2 Definitions Biochemical evolution: study of how proteins (and other molecules) and biochemical pathways have changed through time. Homologous proteins: proteins with a significant degree of sequence similarity ----or---- proteins that share a common function Characterisitics: sequence similarity polypeptides chain lengths similar amount of sequence identity = evolutionary relatedness Divergent evolution: Proteins derived from common ancestors Sequence Alignment: Identification of homologous proteins cytochrome c: a favorite example Yellow - invariant; blue - conservative; unshaded; non-conserved

3 Comparison of sequence differences # of differences is proportional to the phylogenetic difference Phylogenetic trees: evolutionary relatedness # of changes is proportional to evolutionary time since the common ancestor

4 How human cyt c compares with its ancestral progenitor Conservation in structure A). Tuna (5cyt) B). Tuna C). Rice (1cc4) D). Yeast(1ycc) E). Bacterial (1hro)

5 The Globins: the oxygen binding heme proteins PHYLOGENETIC TREE FOR THE GLOBINS * * * * * gene duplication events play a major role here!

6 Tertiary structure is more conserved than primary structure Convergent evolution: different evolutionary paths lead to the same solution The serine proteases: cleave peptide bonds by hydrolysis Active sites Protein structure mostly β-sheet mix α/β

7 Genetic Variability Gene mutations (base substitutions) can lead to altered amino acid substitutions; can be neutral, aberrant or nonfunctional Hb S: Sickle cell Hb Hb S: A case study Sickle hemoglobin (HbS); Mutation β6 E -> V; Most common in people of African and Caribbean descent 1 in carry the trait 1 in have the disease High incidence of sickle cell allele generally coincides with high incidence of malaria; Heterozygotes have a higher resistance to malaria; The fragility of the RBCs tends to interrupt the malarias life cycle; Therefore, heterozygotes have a higher survival rate & are more likely to pass on their genes!

8 Structural consequence of the mutation β6 glutamic acid --> valine mutation Hydrophobic groups don t like to be solvent-exposed! Valine fits nicely into the hydrophobic pocket on an adjacent hemoglobin molecule; the pocket is accessible in deoxy Hb Structural consequence of the mutation β6 glutamic acid --> valine mutation

9 Classification: we ve seen this Enzymes - catalyze chemical reactions Regulatory proteins - control physiological function Transport proteins - move substances around/between cells Storage proteins - provide a reservoir for a substance Motor proteins - endow cells with capability of movement Structural proteins - create and maintain biological structure Protective proteins -active role in cell defense or protection Exotic proteins - have specialized adaptive functions DNA binding proteins - regulation of gene expression Signalling Proteins - convert extracellular signal into intracellular response The simplification: And all this with just 20 amino acids and some post-translational modifications! The reality: many proteins contain other chemical groups Conjugated Proteins Nomenclature: the word "conjugated" is from the Latin, con = with jugum = yoke Thus, the protein and non-protein moieties are yoked with one another (like oxen) to work together. Apoprotein = the protein without its non-protein component; Prosthetic group = the non-protein portion alone;what we call the non-amino acid component if it is crucial to function or influences the conformation of the protein. Conjugated or holo- protein = the apoprotein + prosthetic group.

10 Classification of conjugated proteins Glycoproteins Lipoproteins Nucleoproteins Phosphoproteins Metalloproteins Hemoproteins Flavoproteins Examples of Prosthetic Groups Heme Phosphate Carbohydrate Lipid Stephen Everse 2001

11 REVIEW 1). Sequence similarities between proteins imply evolutionary relatedness. 2). Homologous proteins are those that perform the same function in different organisms. 3). Related proteins are that have related functions. 4). Invariant amino acids are crucial to either structure or function. 5). The number of sequence changes in homologous proteins is proportional to the phylogenetic difference between the organisms. 6). Length of branches in phylogenetic trees are proportional to time. 7). Conservation of sequence is followed by conservation of structure. 8). Genetic variability exist in large populations. 9). Proteins can be classified according to function or chemistry. 10). Familiarize yourself with the classifications!