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The Relationship between Oligomeric State and Protein Function

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Book cover Protein Dimerization and Oligomerization in Biology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 747))

Abstract

The reason that many proteins adopt a particular oligomeric form is far from obvious. In this chapter, we discuss potential advantages of proteins self-assembling into specific quaternary structures. A number of case studies are presented in which wild-type proteins have been mutated to generate variants of lower oligomeric order and the impact on the resulting proteins, in terms of both specific function and generic stability, are discussed. Drawing on these case studies, some general design principles for quaternary structure engineering are put forward to facilitate these experiments on a wider range of systems. It is clear that the advantages afforded by quaternary structure vary from protein to protein; however, some general trends are starting to emerge.

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References

  1. Eisenstein E, Schachman HK. Determining the roles of subunits in protein function. In: Creighton TE, ed. Protein Function. Oxford: IRL Press, 1989.

    Google Scholar 

  2. Perham RN. Self-assembly of biological macromolecules. Philos Trans R Soc Lond B Biol Sci 1975; 272(915):123–136.

    Article  PubMed  CAS  Google Scholar 

  3. Marianayagam NJ, Sunde M, Matthews JM. The power of two: protein dimerization in biology. Trends Biochem Sci 2004; 29(11):618–625.

    Article  PubMed  CAS  Google Scholar 

  4. Ali MH, Imperiali B. Protein oligomerization: How and why. Bioorg Med Chem 2005; 13(17):5013–5020.

    Article  PubMed  CAS  Google Scholar 

  5. Klotz IM, Darnall DW, Langerman NR. Quaternary structure of proteins. In: Hill RL, ed. The proteins. New York: Academic Press, 1975.

    Google Scholar 

  6. Beernink PT, Tolan DR. Disruption of the aldolase A tetramer into catalytically active monomers. Proc Natl Acad Sci USA 1996; 93(11):5374–5379.

    Article  PubMed  CAS  Google Scholar 

  7. Traut TW. Dissociation of enzyme oligomers: a mechanism for allosteric regulation. Crit Rev Biochem Mol Biol 1994; 29(2):125–163.

    Article  PubMed  CAS  Google Scholar 

  8. Monod J, Wyman J, Changeux JP. On the nature of allosteric transitions: a plausible model. J Mol Biol 1965:128–118.

    Google Scholar 

  9. Nooren IM, Thornton JM. Diversity of protein-protein interactions. EMBO J 2003; 22(14):3486–3492.

    Article  PubMed  CAS  Google Scholar 

  10. Goodsell DS, Olson AJ. Structural symmetry and protein function. Annu Rev Biophys Biomol Struct 2000:2905–153.

    Google Scholar 

  11. Ponstingl H, Thomas KB, Gorse D et al. Morphological aspects of oligorneric protein structures. Prog Biophys Mol Biol 2005; 89(1):9–35.

    Article  PubMed  CAS  Google Scholar 

  12. Papoian GA, Ulander J, Wolynes PG. Role of water mediated interactions in protein-protein recognition landscapes. J Am Chem Soc 2003; 125(30):9170–9178.

    Article  PubMed  CAS  Google Scholar 

  13. Ma B, Elkayam T, Wolfson H et al. Protein-protein interactions: structurally conserved residues distinguish between binding sites and exposed protein surfaces. Proc Natl Acad Sci, USA 2003; 100(10):5772–5777.

    Article  PubMed  CAS  Google Scholar 

  14. Ofran Y, Rost B. Analysing six types of protein-protein interfaces. J Mol Biol 2003; 325(2):377–387.

    Article  PubMed  CAS  Google Scholar 

  15. Jones S, Thornton JM. Principles of protein-protein interactions. Proc Natl Acad Sci, USA 1996; 93(1):13–20.

    Article  PubMed  CAS  Google Scholar 

  16. Jones S, Thornton JM. Analysis of protein-protein interaction sites using surface patches. J Mol Biol 1997; 272(1):121–132.

    Article  PubMed  CAS  Google Scholar 

  17. Jones S, Thornton JM. Protein-protein interactions: a review of protein dimer structures. Prog Biophys Mol Biol 1995; 63(1):31–65.

    Article  PubMed  CAS  Google Scholar 

  18. Lo Conte L, Chothia C, Janin J. The atomic structure of protein-protein recognition sites. J Mol Biol 1999; 285(5):2177–2198.

    Article  PubMed  Google Scholar 

  19. Nooren IM, Thornton JM.Structural characterisation and functional significance of transient protein-protein interactions. J Mol Biol 2003; 325(5):991–1018.

    Article  PubMed  CAS  Google Scholar 

  20. Jones S, Thornton JM. Prediction of protein-protein interaction sites using patch analysis. J Mol Biol 1997; 272(1):133–143.

    Article  PubMed  CAS  Google Scholar 

  21. Salwinski L, Eisenberg D. Computational methods of analysis of protein-protein interactions. Curr Opin Struct Biol 2003; 13(3):377–382.

    Article  PubMed  CAS  Google Scholar 

  22. Ofran Y, Rost B. Predicted protein-protein interaction sites from local sequence information. FEBS Lett 2003; 544(1–3):236–239.

    Article  PubMed  CAS  Google Scholar 

  23. Brooijmans N, Sharp KA, Kuntz ID. Stability of macromolecular complexes. Proteins 2002; 48(4):645–653.

    Article  PubMed  CAS  Google Scholar 

  24. Perutz MF. Science is not a quiet life: Unravelling the atomic mechanism of haemoglobin. Singapore: Imperial College Press, 1997.

    Google Scholar 

  25. Perugini MA, Griffin MDW, Smith BJ et al. Insight into the self-association of key enzymes from pathogenic species. Eur Biophys J 2005; 34(5):469–476.

    Article  PubMed  CAS  Google Scholar 

  26. Kim SY, Kim YW, Hegerl R et al. Novel type of enzyme multimerization enhances substrate affinity of oat beta-glucosidase. J Struct Biol 2005; 150(1):1–10.

    Article  PubMed  CAS  Google Scholar 

  27. Franke I, Meiss G, Blecher D et al. Genetic engineering, production and characterisation of monomeric variants of the dimeric Serratia marcescens endonuclease. FEBS Lett 1998; 425(3):517–522.

    Article  PubMed  CAS  Google Scholar 

  28. Mossing MC, Sauer RT. Stable, monomeric variants of α Cro obtained by insertion of a designed β-hairpin sequence. Science 1990; 250(4988):1712–1715.

    Article  PubMed  CAS  Google Scholar 

  29. Borchert TV, Abagyan R, Jaenicke R et al. Design, creation and characterization of a stable, monomeric triosephosphate isomerase. Proc Natl Acad Sci, USA 1994; 91(4):1515–1518.

    Article  PubMed  CAS  Google Scholar 

  30. Jackson RM, Gelpi JL, Cortes A et al. Construction of a stable dimer of Bacillus stearothermophilus lactate dehydrogenase. Biochemistry 1992; 31(35):8307–8314.

    Article  PubMed  CAS  Google Scholar 

  31. Dobson CM. Getting out of shape. Nature 2002; 418(6899):729–730.

    Article  PubMed  CAS  Google Scholar 

  32. Nielsen L, Khurana R, Coats A et al. Effect of environmental factors on the kinetics of insulin fibril formation: elucidation of the molecular mechanism. Biochemistry 2001; 40(20):6036–6046.

    Article  PubMed  CAS  Google Scholar 

  33. Lashuel HA, Lai Z, Kelly JW. Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation: implications for wild-type, V30M and L55P amyloid fibril formation. Biochemistry 1998; 37(51):17851–17864.

    Article  PubMed  CAS  Google Scholar 

  34. Foss TR, Kelker MS, Wiseman RL et al. Kinetic stabilization of the native state by protein engineering: Implications for inhibition of transthyretin amyloidogenesis. J Mol Biol 2005; 347(4):841–854.

    Article  PubMed  CAS  Google Scholar 

  35. Thorn DC, Meehan S, Sunde M et al. Amyloid fibril formation by bovine milk kappa-casein and its inhibition by the molecular chaperones alpha(s-) and beta-casein. Biochemistry 2005; 44(51):17027–17036.

    Article  PubMed  CAS  Google Scholar 

  36. Souillac PO, Uversky VN, Fink AL. Structural transformations of oligomeric intermediates in the fibrillation of the immunoglobulin light chain LEN. Biochemistry 2003; 42(26):8094–8104.

    Article  PubMed  CAS  Google Scholar 

  37. Raghu P, Reddy GB, Sivakumar B. Inhibition of transthyretin amyloid fibril formation by 2,4-dinitrophenol through tetramer stabilization. Arch Biochem Biophys 2002; 400(1):43–47.

    Article  PubMed  CAS  Google Scholar 

  38. Jenne DE, Denzel K, Blatzinger P et al. A new isoleucine substitution of Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis. Proc Natl Acad Sci USA 1996; 93(13):6302–6307.

    Article  PubMed  CAS  Google Scholar 

  39. Hammarstrom P, Sekijima Y, White JT et al. D18G transthyretin is monomeric, aggregation prone and not detectable in plasma and cerebrospinal fluid: a prescription for central nervous system amyloidosis? Biochemistry 2003; 42(22):6656–6663.

    Article  PubMed  Google Scholar 

  40. Clegg JS. Properties and metabolism of the aqueous cytoplasm and its boundaries. Am J Physiol 1984; 246(2 Pt 2):R133–151.

    PubMed  CAS  Google Scholar 

  41. Makhatadze GI, Loladze VV, Ermolenko DN et al. Contribution of surface salt bridges to protein stability: guidelines for protein engineering. J Mol Biol 2003; 327(5):1135–1148.

    Article  PubMed  CAS  Google Scholar 

  42. Karshikoff A, Ladenstein R. Ion pairs and the thermotolerance of proteins from hyperthermophiles: a “traffic rule” for hot roads. Trends Biochem Sci 2001; 26(9):550–556.

    Article  PubMed  CAS  Google Scholar 

  43. Yip KS, Britton KL, Stillman TJ et al. Insights into the molecular basis of thermal stability from the analysis of ion-pair networks in the glutamate dehydrogenase family. Eur J Biochem 1998; 255(2):336–346.

    Article  PubMed  CAS  Google Scholar 

  44. Gerk LP, Leven O, Muller-Hill B. Strengthening the dimerisation interface of Lac repressor increases its thermostability by 40°C. J Mol Biol 2000; 299(3):805–812.

    Article  PubMed  CAS  Google Scholar 

  45. Vetriani C, Maeder DL, Tolliday N et al. Protein thermostability above 100°C: a key role for ionic interactions. Proc Natl Acad Sci USA 1998; 95(21):12300–12305.

    Article  PubMed  CAS  Google Scholar 

  46. Lebbink JH, Knapp S, van der Oost J et al. Engineering activity and stability of Thermotoga maritima glutamate dehydrogenase. II: construction of a 16-residue ion-pair network at the subunit interface. J Mol Biol 1999; 289(2):357–369.

    Article  PubMed  CAS  Google Scholar 

  47. Kou H, Pugh BF. Engineering dimer-stabilizing mutations in the TATA-binding protein. J Biol Chem 2004; 279(20):20966–20973.

    Article  PubMed  CAS  Google Scholar 

  48. Ahern TJ, Casal JI, Petsko GA et al. Control of oligomeric enzyme thermostability by protein engineering. Proc Natl Acad Sci USA 1987; 84(3):675–679.

    Article  PubMed  CAS  Google Scholar 

  49. Casal JI, Ahern TJ, Davenport RC et al. Subunit interface of triosephosphate isomerase: site-directed mutagenesis and characterization of the altered enzyme. Biochemistry 1987; 26(5):1258–1264.

    Article  PubMed  CAS  Google Scholar 

  50. Jones DH, McMillan AJ, Fersht AR et al. Reversible dissociation of dimeric tyrosyl-tRNA synthetase by mutagenesis at the subunit interface. Biochemistry 1985; 24(21):5852–5857.

    Article  PubMed  CAS  Google Scholar 

  51. Ward WH, Jones DH, Fersht AR. Protein engineering of homodimeric tyrosyl-tRNA synthetase to produce active heterodimers. J Biol Chem 1986; 261(21):9576–9578.

    PubMed  CAS  Google Scholar 

  52. Ward WH, Jones DH, Fersht AR. Effects of engineering complementary charged residues into the hydrophobic subunit interface of tyrosyl-tRNA synthetase. Appendix: Kinetic analysis of dimeric enzymes that reversibly dissociate into inactive subunits. Biochemistry 1987; 26(13):4131–4138.

    Article  PubMed  CAS  Google Scholar 

  53. Carter P, Bedouelle H, Winter G. Construction of heterodimer tyrosyl-tRNA synthetase shows tRNATyr interacts with both subunits. Proc Natl Acad Sci USA 1986; 83(5):1189–1192.

    Article  PubMed  CAS  Google Scholar 

  54. Vora JP, Owens DR, Dolben J et al. Recombinant DNA derived monomeric insulin analogue: Comparison with soluble human insulin in normal subjects. Bmj 1988; 297(6658):1236–1239.

    Article  PubMed  CAS  Google Scholar 

  55. Brange J, Ribel U, Hansen JF et al. Monomeric insulins obtained by protein engineering and their medical implications. Nature 1988; 333(6174):679–682.

    Article  PubMed  CAS  Google Scholar 

  56. Hoffman A, Ziv E. Pharmacokinetic considerations of new insulin formulations and routes of administration. Clin Pharmacokinet 1997; 33(4):285–301.

    Article  PubMed  CAS  Google Scholar 

  57. DeFelippis MR, Chance RE, Frank BH. Insulin self-association and the relationship to pharmacokinetics and pharmacodynamics. Crit Rev Ther Drug Carrier Syst 2001; 18(2):201–264.

    Article  PubMed  CAS  Google Scholar 

  58. Miller MD, Krause KL. Identification of the Serratia endonuclease dimer: structural basis and implications for catalysis. Protein Sci 1996; 5(1):24–33.

    Article  PubMed  CAS  Google Scholar 

  59. Franke I, Meiss G, Pingoud A. On the advantage of being a dimer, a case study using the dimeric Serratia nuclease and the monomeric nuclease from Anabaena sp. strain PCC 7120. J Biol Chem 1999; 274(2):825–832.

    Article  PubMed  CAS  Google Scholar 

  60. LeFevre KR, Cordes MHJ. Retroevolution of lambda Cro toward a stable monomer. Proc Natl Acad Sci USA 2003; 100(5):2345–2350.

    Article  PubMed  CAS  Google Scholar 

  61. Borchert TV, Pratt K, Zeelen JP et al. Overexpression of trypanosomal triosephosphate isomerase in Escherichia coli and characterisation of a dimer-interface mutant. Eur J Biochem 1993; 211(3):703–710.

    Article  PubMed  CAS  Google Scholar 

  62. Borchert TV, Zeelen JP, Schliebs W et al. An interface point-mutation variant of triosephosphate isomerase is compactly folded and monomeric at low protein concentrations. FEBS Lett 1995; 367(3):315–318.

    Article  PubMed  CAS  Google Scholar 

  63. Borchert TV, Abagyan R, Kishan KVR et al. The crystal structure of an engineered monomeric triosephosphate isomerase, monoTIM: the correct modeling of an 8-residue loop. Structure 1993; 1(3):205–213.

    Article  PubMed  CAS  Google Scholar 

  64. Olivares-Illana V, Perez-Montfort R, Lopez-Calahorra F et al. Structural differences in triosephosphate isomerase from different species and discovery of a multitrypanosomatid inhibitor. Biochemistry 2006; 45(8):2556–2560.

    Article  PubMed  CAS  Google Scholar 

  65. Berg T. Modulation of protein-protein interactions with small organic molecules. Angew Chem-Int Edit 2003; 42(22):2462–2481.

    Article  CAS  Google Scholar 

  66. Ryan DP, Matthews JM. Protein-protein interactions in human disease. Curr Opin Struct Biol 2005; 15(4):441–446.

    Article  PubMed  CAS  Google Scholar 

  67. Arkin MR, Wells JA. Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream. Nat Rev Drug Discov 2004; 3(4):301–317.

    Article  PubMed  CAS  Google Scholar 

  68. Schliebs W, Thanki N, Jaenicke R et al. A double mutation at the tip of the dimer interface loop of triosephosphate isomerase generates active monomers with reduced stability. Biochemistry 1997; 36(32):9655–9662.

    Article  PubMed  CAS  Google Scholar 

  69. Borchert TV, Kishan KV, Zeelen JP et al. Three new crystal structures of point mutation variants of monoTIM: conformational flexibility of loop-1, loop-4 and loop-8. Structure 1995; 3(7):669–679.

    Article  PubMed  CAS  Google Scholar 

  70. Mainfroid V, Terpstra P, Beauregard M et al. Three hTIM mutants that provide new insights on why TIM is a dimer. J Mol Biol 1996; 257(2):441–456.

    Article  PubMed  CAS  Google Scholar 

  71. Mainfroid V, Mande SC, Hol WG et al. Stabilization of human triosephosphate isomerase by improvement of the stability of individual a-helices in dimeric as well as monomeric forms of the protein. Biochemistry 1996; 35(13):4110–4117.

    Article  PubMed  CAS  Google Scholar 

  72. McKenzie AN, Ely B, Sanderson CJ. Mutated interleukin-5 monomers are biologically inactive. Mol Immunol 1991; 28(1–2):155–158.

    Article  PubMed  CAS  Google Scholar 

  73. Dickason RR, Huston DP. Creation of a biologically active interleukin-5 monomer. Nature 1996; 379(6566):652–655.

    Article  PubMed  CAS  Google Scholar 

  74. Sano T, Vajda S, Smith CL et al. Engineering subunit association of multisubunit proteins: a dimeric streptavidin. Proc Natl Acad Sci USA 1997; 94(12):6153–6158.

    Article  PubMed  CAS  Google Scholar 

  75. Pazy Y, Eisenberg-Domovich Y, Laitinen OH et al. Dimer-tetramer transition between solution and crystalline states of streptavidin and avidin mutants. J Bacteriol 2003; 185(14):4050–4056.

    Article  PubMed  CAS  Google Scholar 

  76. Laitinen OH, Nordlund HR, Hytonen VP et al. Rational design of an active avidin monomer. J Biol Chem 2003; 278(6):4010–4014.

    Article  PubMed  CAS  Google Scholar 

  77. Velichko IS, Mikalahti K, Kasho VN et al. Trimeric inorganic pyrophosphatase of Escherichia coli obtained by directed mutagenesis. Biochemistry 1998; 37(2):734–740.

    Article  PubMed  CAS  Google Scholar 

  78. Salminen A, Efimova IS, Parfenyev AN et al. Reciprocal effects of substitutions at the subunit interfaces in hexameric pyrophosphatase of Escherichia coli. Dimeric and monomeric forms of the enzyme. J Biol Chem 1999; 274(48):33898–33904.

    Article  PubMed  CAS  Google Scholar 

  79. Fritsche P, Alves J. A monomeric mutant of restriction endonuclease EcoR I nicks DNA without sequence specificity. Biol Chem 2004; 385(10):975–985.

    Article  PubMed  CAS  Google Scholar 

  80. Zaremba M, Sasnauskas G, Urbanke C et al. Conversion of the tetrameric restriction endonuclease Bse634I into a dimer: Oligomeric structure-stability-function correlations. J Mol Biol 2005; 348(2):459–478.

    Article  PubMed  CAS  Google Scholar 

  81. Banci L, Benedetto M, Bertini I et al. Solution structure of reduced monomeric Q133M2 copper, zinc superoxide dismutase (SOD). Why is SOD a dimeric enzyme? Biochemistry 1998; 37(34):11780–11791.

    Article  PubMed  CAS  Google Scholar 

  82. Banci L, Bertini I, Chiu CY et al. Synthesis and characterization of a monomeric mutant Cu/Zn superoxide dismutase with partially reconstituted enzymic activity. Eur J Biochem 1995; 234(3):855–860.

    Article  PubMed  CAS  Google Scholar 

  83. Porvari KS, Herrala AM, Kurkela RM et al. Site-directed mutagenesis of prostatic acid phosphatase. Catalytically important aspartic acid 258, substrate specificity and oligomerization. J Biol Chem 1994; 269(36):22642–22646.

    PubMed  CAS  Google Scholar 

  84. Breiter DR, Resnik E, Banaszak LJ. Engineering the quaternary structure of an enzyme: construction and analysis of a monomeric form of malate dehydrogenase from Escherichia coli. Protein Sci 1994; 3(11):2023–2032.

    Article  PubMed  CAS  Google Scholar 

  85. Beernink PT, Tolan DR. Subunit interface mutants of rabbit muscle aldolase form active dimers. Protein Sci 1994; 3(9):1383–1391.

    Article  PubMed  CAS  Google Scholar 

  86. Beernink PT, Tolan DR. Disruption of the aldolase A tetramer into catalytically active monomers. Proc Natl Acad Sci USA 1996; 93(11):5374–5379.

    Article  PubMed  CAS  Google Scholar 

  87. Bailey DL, Fraser ME, Bridger WA et al. A dimeric form of Escherichia coli succinyl-CoA synthetase produced by site-directed mutagenesis. J Mol Biol 1999; 285(4):1655–1666.

    Article  PubMed  CAS  Google Scholar 

  88. Griffin MDW, Dobson RCJ, Pearce FG et al. Evolution of quaternary structure in a homotetrameric enzyme. J Mol Biol 2008; 380(4): 691–703.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Melbourne, Victoria, Australia

    Michael D. W. Griffin

  2. Biomolecular Interaction Centre (BIC), School of Biological Sciences, University of Canterbury, Christchurch, New Zealand

    Juliet A. Gerrard

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  1. Michael D. W. Griffin
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  2. Juliet A. Gerrard
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Correspondence to Juliet A. Gerrard .

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  1. School of Molecular Bioscience, University of Sydney, Sydney, Australia

    Jacqueline M. Matthews PhD

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Griffin, M.D.W., Gerrard, J.A. (2012). The Relationship between Oligomeric State and Protein Function. In: Matthews, J.M. (eds) Protein Dimerization and Oligomerization in Biology. Advances in Experimental Medicine and Biology, vol 747. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3229-6_5

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