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Structure and stability effects of mutations designed to increase the primary sequence symmetry within the core region of a beta-trefoil.

Brych SR, Blaber SI, Logan TM, Blaber M
Protein Sci 10 2587-99 (2001)
Related entries: 1jqz, 1jt3, 1jt4, 1jt7, 1jtc

Cited: 48 times
EuropePMC logo PMID: 11714927

Abstract

Human acidic fibroblast growth factor (FGF-1) is a member of the beta-trefoil hyperfamily and exhibits a characteristic threefold symmetry of the tertiary structure. However, evidence of this symmetry is not readily apparent at the level of the primary sequence. This suggests that while selective pressures may exist to retain (or converge upon) a symmetric tertiary structure, other selective pressures have resulted in divergence of the primary sequence during evolution. Using intra-chain and homologue sequence comparisons for 19 members of this family of proteins, we have designed mutants of FGF-1 that constrain a subset of core-packing residues to threefold symmetry at the level of the primary sequence. The consequences of these mutations regarding structure and stability were evaluated using a combination of X-ray crystallography and differential scanning calorimetry. The mutational effects on structure and stability can be rationalized through the characterization of "microcavities" within the core detected using a 1.0A probe radius. The results show that the symmetric constraint within the primary sequence is compatible with a well-packed core and near wild-type stability. However, despite the general maintenance of overall thermal stability, a noticeable increase in non-two-state denaturation follows the increase in primary sequence symmetry. Therefore, properties of folding, rather than stability, may contribute to the selective pressure for asymmetric primary core sequences within symmetric protein architectures.

Reviews citing this publication (3)

  1. FGF-1: from biology through engineering to potential medical applications. Zakrzewska M, Marcinkowska E, Wiedlocha A. Crit Rev Clin Lab Sci 45 91-135 (2008)
  2. Protein engineering for cardiovascular therapeutics: untapped potential for cardiac repair. Jay SM, Lee RT. Circ Res 113 933-943 (2013)
  3. Emergence of symmetric protein architecture from a simple peptide motif: evolutionary models. Blaber M, Lee J, Longo L. Cell Mol Life Sci 69 3999-4006 (2012)

Articles citing this publication (45)

  1. Experimental support for the evolution of symmetric protein architecture from a simple peptide motif. Lee J, Blaber M. Proc Natl Acad Sci U S A 108 126-130 (2011)
  2. Highly stable mutants of human fibroblast growth factor-1 exhibit prolonged biological action. Zakrzewska M, Krowarsch D, Wiedlocha A, Olsnes S, Otlewski J. J Mol Biol 352 860-875 (2005)
  3. A polypeptide "building block" for the β-trefoil fold identified by "top-down symmetric deconstruction". Lee J, Blaber SI, Dubey VK, Blaber M. J Mol Biol 407 744-763 (2011)
  4. Clusters of isoleucine, leucine, and valine side chains define cores of stability in high-energy states of globular proteins: Sequence determinants of structure and stability. Kathuria SV, Chan YH, Nobrega RP, Özen A, Matthews CR. Protein Sci 25 662-675 (2016)
  5. Identification of a key structural element for protein folding within beta-hairpin turns. Kim J, Brych SR, Lee J, Logan TM, Blaber M. J Mol Biol 328 951-961 (2003)
  6. A novel β-trefoil lectin from the parasol mushroom (Macrolepiota procera) is nematotoxic. Žurga S, Pohleven J, Renko M, Bleuler-Martinez S, Sosnowski P, Turk D, Künzler M, Kos J, Sabotič J. FEBS J 281 3489-3506 (2014)
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  8. Symmetric primary and tertiary structure mutations within a symmetric superfold: a solution, not a constraint, to achieve a foldable polypeptide. Brych SR, Dubey VK, Bienkiewicz E, Lee J, Logan TM, Blaber M. J Mol Biol 344 769-780 (2004)
  9. An atomic resolution structure for human fibroblast growth factor 1. Bernett MJ, Somasundaram T, Blaber M. Proteins 57 626-634 (2004)
  10. The interaction between thermodynamic stability and buried free cysteines in regulating the functional half-life of fibroblast growth factor-1. Lee J, Blaber M. J Mol Biol 393 113-127 (2009)
  11. Common occurrence of internal repeat symmetry in membrane proteins. Choi S, Jeon J, Yang JS, Kim S. Proteins 71 68-80 (2008)
  12. Experimental support for the foldability-function tradeoff hypothesis: segregation of the folding nucleus and functional regions in fibroblast growth factor-1. Longo L, Lee J, Blaber M. Protein Sci 21 1911-1920 (2012)
  13. A logical OR redundancy within the Asx-Pro-Asx-Gly type I beta-turn motif. Lee J, Dubey VK, Longo LM, Blaber M. J Mol Biol 377 1251-1264 (2008)
  14. Accommodation of a highly symmetric core within a symmetric protein superfold. Brych SR, Kim J, Logan TM, Blaber M. Protein Sci 12 2704-2718 (2003)
  15. An empirical phase diagram approach to investigate conformational stability of "second-generation" functional mutants of acidic fibroblast growth factor-1. Alsenaidy MA, Wang T, Kim JH, Joshi SB, Lee J, Blaber M, Volkin DB, Middaugh CR. Protein Sci 21 418-432 (2012)
  16. A common sequence-associated physicochemical feature for proteins of beta-trefoil family. Xu R, Xiao Y. Comput Biol Chem 29 79-82 (2005)
  17. Redesigning symmetry-related "mini-core" regions of FGF-1 to increase primary structure symmetry: thermodynamic and functional consequences of structural symmetry. Dubey VK, Lee J, Blaber M. Protein Sci 14 2315-2323 (2005)
  18. PROTS: a fragment based protein thermo-stability potential. Li Y, Zhang J, Tai D, Middaugh CR, Zhang Y, Fang J. Proteins 80 81-92 (2012)
  19. Structural basis of conserved cysteine in the fibroblast growth factor family: evidence for a vestigial half-cystine. Lee J, Blaber M. J Mol Biol 393 128-139 (2009)
  20. Non-linear effects of temperature and urea on the thermodynamics and kinetics of folding and unfolding of hisactophilin. Wong HJ, Stathopulos PB, Bonner JM, Sawyer M, Meiering EM. J Mol Biol 344 1089-1107 (2004)
  21. Pharmacokinetic properties of 2nd-generation fibroblast growth factor-1 mutants for therapeutic application. Xia X, Babcock JP, Blaber SI, Harper KM, Blaber M. PLoS One 7 e48210 (2012)
  22. A single aromatic core mutation converts a designed "primitive" protein from halophile to mesophile folding. Longo LM, Tenorio CA, Kumru OS, Middaugh CR, Blaber M. Protein Sci 24 27-37 (2015)
  23. Interaction of anti-aggregation agent dimethylethylammonium propane sulfonate with acidic fibroblast growth factor. Xiang L, Ishii T, Hosoda K, Kamiya A, Enomoto M, Nameki N, Inoue Y, Kubota K, Kohno T, Wakamatsu K. J Magn Reson 194 147-151 (2008)
  24. Symmetric key structural residues in symmetric proteins with beta-trefoil fold. Feng J, Li M, Huang Y, Xiao Y. PLoS One 5 e14138 (2010)
  25. Alternative folding nuclei definitions facilitate the evolution of a symmetric protein fold from a smaller peptide motif. Longo LM, Lee J, Tenorio CA, Blaber M. Structure 21 2042-2050 (2013)
  26. Purification and characterization of the beta-trefoil fold protein barley alpha-amylase/subtilisin inhibitor overexpressed in Escherichia coli. Bønsager BC, Praetorius-Ibba M, Nielsen PK, Svensson B. Protein Expr Purif 30 185-193 (2003)
  27. Ab initio folding of a trefoil-fold motif reveals structural similarity with a β-propeller blade motif. Tenorio CA, Longo LM, Parker JB, Lee J, Blaber M. Protein Sci 29 1172-1185 (2020)
  28. Hidden symmetries in the primary sequences of beta-barrel family. Ji X, Chen H, Xiao Y. Comput Biol Chem 31 61-63 (2007)
  29. Alternative type I and I' turn conformations in the beta8/beta9 beta-hairpin of human acidic fibroblast growth factor. Kim J, Blaber SI, Blaber M. Protein Sci 11 459-466 (2002)
  30. Conserved buried water molecules enable the β-trefoil architecture. Blaber M. Protein Sci 29 1794-1802 (2020)
  31. Proteins with simplified hydrophobic cores compared to other packing mutants. Chen J, Lu Z, Sakon J, Stites WE. Biophys Chem 110 239-248 (2004)
  32. Sequence swapping does not result in conformation swapping for the beta4/beta5 and beta8/beta9 beta-hairpin turns in human acidic fibroblast growth factor. Kim J, Lee J, Brych SR, Logan TM, Blaber M. Protein Sci 14 351-359 (2005)
  33. Conversion of type I 4:6 to 3:5 beta-turn types in human acidic fibroblast growth factor: effects upon structure, stability, folding, and mitogenic function. Lee J, Dubey VK, Somasundaram T, Blaber M. Proteins 62 686-697 (2006)
  34. Effect of extension of the heparin binding pocket on the structure, stability, and cell proliferation activity of the human acidic fibroblast growth factor. Davis JE, Gundampati RK, Jayanthi S, Anderson J, Pickhardt A, Koppolu BP, Zaharoff DA, Kumar TKS. Biochem Biophys Rep 13 45-57 (2018)
  35. Engineering a Cysteine-Free Form of Human Fibroblast Growth Factor-1 for "Second Generation" Therapeutic Application. Xia X, Kumru OS, Blaber SI, Middaugh CR, Li L, Ornitz DM, Sutherland MA, Tenorio CA, Blaber M. J Pharm Sci 105 1444-1453 (2016)
  36. Cooperative hydrophobic core interactions in the β-trefoil architecture. Blaber M. Protein Sci 30 956-965 (2021)
  37. Oligomerization of a symmetric β-trefoil protein in response to folding nucleus perturbation. Tenorio CA, Parker JB, Blaber M. Protein Sci 29 1629-1640 (2020)
  38. Structure of rat acidic fibroblast growth factor at 1.4 A resolution. Kulahin N, Kiselyov V, Kochoyan A, Kristensen O, Kastrup JS, Berezin V, Bock E, Gajhede M. Acta Crystallogr Sect F Struct Biol Cryst Commun 63 65-68 (2007)
  39. Effects of external interactions on protein sequence-structure relations of beta-trefoil fold. Li M, Huang Y, Xiao Y. Proteins 72 1161-1170 (2008)
  40. Functionalization of a symmetric protein scaffold: Redundant folding nuclei and alternative oligomeric folding pathways. Tenorio CA, Parker JB, Blaber M. Protein Sci 31 e4301 (2022)
  41. Mutagenesis of the crystal contact of acidic fibroblast growth factor. Honjo E, Tamada T, Adachi M, Kuroki R, Meher A, Blaber M. J Synchrotron Radiat 15 285-287 (2008)
  42. An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities. Xia X, Kumru OS, Blaber SI, Middaugh CR, Li L, Ornitz DM, Suh JM, Atkins AR, Downes M, Evans RM, Tenorio CA, Bienkiewicz E, Blaber M. J Pharm Sci 105 3507-3519 (2016)
  43. Engineering the kinetic stability of a β-trefoil protein by tuning its topological complexity. Anderson DM, Jayanthi LP, Gosavi S, Meiering EM. Front Mol Biosci 10 1021733 (2023)
  44. Fine-Sampled Photographic Quantitation of Dermal Wound Healing Senescence in Aged BALB/cByJ Mice and Therapeutic Intervention with Fibroblast Growth Factor-1. Mellers AP, Tenorio CA, Lacatusu DA, Powell BD, Patel BN, Harper KM, Blaber M. Adv Wound Care (New Rochelle) 7 409-418 (2018)
  45. Investigating the dynamics and polyanion binding sites of fibroblast growth factor-1 using hydrogen-deuterium exchange mass spectrometry. Angalakurthi SK, Tenorio CA, Blaber M, Middaugh CR. Protein Sci 27 1068-1082 (2018)


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