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Dissecting the energetics of protein alpha-helix C-cap termination through chemical protein synthesis.

Bang D, Gribenko AV, Tereshko V, Kossiakoff AA, Kent SB, Makhatadze GI
Nat Chem Biol 2 139-43 (2006)
Related entries: 2fcm, 2fcq, 2fcs

Cited: 45 times
EuropePMC logo PMID: 16446709

Abstract

The alpha-helix is a fundamental protein structural motif and is frequently terminated by a glycine residue. Explanations for the predominance of glycine at the C-cap terminal portions of alpha-helices have invoked uniquely favorable energetics of this residue in a left-handed conformation or enhanced solvation of the peptide backbone because of the absence of a side chain. Attempts to quantify the contributions of these two effects have been made previously, but the issue remains unresolved. Here we have used chemical protein synthesis to dissect the energetic basis of alpha-helix termination by comparing a series of ubiquitin variants containing an L-amino acid or the corresponding D-amino acid at the C-cap Gly35 position. D-Amino acids can adopt a left-handed conformation without energetic penalty, so the contributions of conformational strain and backbone solvation can thus be separated. Analysis of the thermodynamic data revealed that the preference for glycine at the C' position of a helix is predominantly a conformational effect.

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  18. The role of protein homochirality in shaping the energy landscape of folding. Nanda V, Andrianarijaona A, Narayanan C. Protein Sci 16 1667-1675 (2007)
  19. SnapDock-template-based docking by Geometric Hashing. Estrin M, Wolfson HJ. Bioinformatics 33 i30-i36 (2017)
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  21. Total chemical synthesis and biophysical characterization of the minimal isoform of the KChIP2 potassium channel regulatory subunit. Rajagopal S, Kent SB. Protein Sci 16 2056-2064 (2007)
  22. Mapping side chain interactions at protein helix termini. Newell NE. BMC Bioinformatics 16 231 (2015)
  23. Mirrors in the PDB: left-handed alpha-turns guide design with D-amino acids. Annavarapu S, Nanda V. BMC Struct Biol 9 61 (2009)
  24. CAPS-DB: a structural classification of helix-capping motifs. Segura J, Oliva B, Fernandez-Fuentes N. Nucleic Acids Res 40 D479-85 (2012)
  25. Comment Lifting the lid on helix-capping. Rose GD. Nat Chem Biol 2 123-124 (2006)
  26. Using D-Amino Acids to Delineate the Mechanism of Protein Folding: Application to Trp-cage. Culik RM, Annavarapu S, Nanda V, Gai F. Chem Phys 422 (2013)
  27. Exploring the Functional Consequences of Protein Backbone Alteration in Ubiquitin through Native Chemical Ligation. Werner HM, Estabrooks SK, Preston GM, Brodsky JL, Horne WS. Chembiochem 20 2346-2350 (2019)
  28. Conformational editing of intrinsically disordered protein by α-methylation. Bauer V, Schmidtgall B, Gógl G, Dolenc J, Osz J, Nominé Y, Kostmann C, Cousido-Siah A, Mitschler A, Rochel N, Travé G, Kieffer B, Torbeev V. Chem Sci 12 1080-1089 (2020)
  29. The leukotriene B4 receptor BLT1 is stabilized by transmembrane helix capping mutations. Hori T, Nakamura M, Yokomizo T, Shimizu T, Miyano M. Biochem Biophys Rep 4 243-249 (2015)
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  32. Implications of the unfolded state in the folding energetics of heterogeneous-backbone protein mimetics. Santhouse JR, Leung JMG, Chong LT, Horne WS. Chem Sci 13 11798-11806 (2022)
  33. Novel <i>DNM1L</i> variants impair mitochondrial dynamics through divergent mechanisms. Nolden KA, Egner JM, Collier JJ, Russell OM, Alston CL, Harwig MC, Widlansky ME, Sasorith S, Barbosa IA, Douglas AG, Baptista J, Walker M, Donnelly DE, Morris AA, Tan HJ, Kurian MA, Gorman K, Mordekar S, Deshpande C, Samanta R, McFarland R, Hill RB, Taylor RW, Oláhová M. Life Sci Alliance 5 e202101284 (2022)
  34. Switching the N-Capping Region from all-L to all-D Amino Acids in a VEGF Mimetic Helical Peptide. De Rosa L, Diana D, Capasso D, Stefania R, Di Stasi R, Fattorusso R, D'Andrea LD. Molecules 27 6982 (2022)


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