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An ancient molecular ancestor for a telomere end binding protein by Martin P. Horvath |
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Protein families are often identified on the basis of sequence similarities. In some cases, when the pedigree is completely masked by amino acid substitutions, a protein's three dimensional structure may preserve features that can place the protein in a particular class of proteins that share a common molecular ancestor. Although amino acid sequence comparisons were only able to relate the Oxytricha nova telomere end binding protein (OnTEBP) to telomere end binding proteins of closely related ciliated protozoa, the structure reveals that OnTEBP is actually a member of a large class of proteins that contain oligonucleotide/oligosaccharide-binding (OB) folds. The OB fold, as originally described for staphylococcal nuclease, the B subunit of E. coli verotoxin-1 and the anticodon-binding domain of aspartyl-tRNA synthetase and subsequently identified in many other proteins including a domain of human replication protein A, consists of five b strands that form two orthogonally packed antiparallel b sheets. The topology of these strands is conserved as S1-S2-S3 for sheet 1 and S1-S4-S5 for sheet 2, with the first strand forming the outer edge of both sheets. An a helix is often found between strands S3 and S4, capping the open edge of this b barrel-like fold. The ligand recognition surface comprises loops connecting strands S1 and S2, strands S3 and S4, and strands S4 and S5 for all currently known OB folds. The corresponding loops found in the four OB folds of the O. nova telomere end binding protein likewise participate in recognizing the single strand telomere DNA or an oligopeptide loop contributed by the b subunit. This scheme of presenting loops at the edge of orthogonally packed b sheets appears to be a general and effective means of generating an extended recognition surface. |
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OB folds present in the O. nova telomere end binding protein. (a)-(d) Four oligonucleotide/oligosaccharide binding folds (OB folds) found in OnTEBP. (a) and (b) the two OB folds that make up the N-terminal DNA-binding domain of a each shown complexed with ssDNA, (c) the single OB fold from the C-terminal domain of a seen interacting with the oligopeptide loop contributed by b, and (d) the more loosely structured OB fold from the b subunit 28 kDa core domain also shown interacting with ssDNA. (e)-(h) The originally described (Murzin, 1993) OB-folds. These are (e) the B subunit of verotoxin-1 from E. coli, (f) the anticodon-binding domain of aspartyl tRNA synthetase shown complexed with tRNA, (g) staphylococcal nuclease complexed with a Ca2+-pTp inhibitor, and (h) fd gene 5 protein. OB folds share a conserved three dimensional structure even though amino acid similarity among family members is weak or absent. The N-terminal b strand S1 (blue) forms the outer edge of both orthogonally packed b sheets. Loops L12, L34, L45, labeled in panel (e), are important for constructing a ligand recognition surface that typically binds extended oligomers such as oligosaccharides, oligonucleotides, or oligopeptides.
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| Proteins with multiple OB folds, such as the single strand binding domain of human replication protein A, array the binding surfaces in tandem to recognize extended oligomers in a non-sequence specific manner. By contrast, the O. nova telomere end binding protein positions three OB folds close together, and this may be a specialized molecular strategy for recognizing bases of the telomere DNA in a sequence specific manner to protect the 3' end of chromosomes. |
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Three of the four OB folds from the Oxytricha nova telomere end binding protein are juxtaposed to create especially deep binding pockets for the 3¹ terminal bases G9-G12 of the single strand telomere DNA. For the DNA, carbon atoms are white, nitrogen atoms are blue, oxygen atoms are red, and phosphorous atoms are yellow.
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1. Horvath, M. P., Schweiker, V. L., Bevilacqua, J. M., Ruggles, J. A. & Schultz, S. C. (1998). Crystal structure of the Oxytricha nova telomere end binding protein complexed with single strand DNA. Cell 95, 963-74. 2. Murzin, A. G. (1993). OB (oligonucleotide/oligosaccharide binding)-fold: common structural and functional solution for non-homologous sequences. Embo J 12, 861-7. |
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Related poster X-ray crystallography by Martin P. Horvath Related poster Crystal structure of a telomere end by Martin P. Horvath, Viloya L. Schweiker, Joanne M. Bevilacqua, James A. Ruggles and Steve C. Schultz To Martin P. Horvath's research interests To a list of all posters in the session |