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Evolution of protein inhibitors of serine proteinases: Positive Darwinian selection or compositional effects?

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In at least two instances involving serine proteinase inhibitors it has been shown that functionally important sites evolve faster and exhibit more interspecific variability than functionally neutral sites. Because these phenomena are difficult to reconcile with the neutral theory of molecular evolution, it has been suggested that the accelerated rate of amino acid substitution at the reactive sites is brought about by positive Darwinian selection. We show that differences in the amino acid composition in the different regions of proteinase inhibitors can account for the differences in the rates of amino acid substitution. By using an index of protein mutability [D. Graur (1985) J Mol Evol 22∶53–62], we show that the amino acid composition of the reactive center in the ovomucoids andSpi-2 gene products is such that, regardless of function, they are expected to evolve more rapidly than any other polypeptide for which the rate of substitution is known. In addition, the reactive region in theSpi-2 proteins is shown to be free of compositional constraint. Positive Darwinian selection need not be invoked at the present time in these cases.

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  1. Barrett AJ, Salvesen G (eds) (1986) Proteinase inhibitors. Elsevier, Amsterdam

  2. Barrett AJ, Nicklin MJH, Rawlings ND (1984) The papain super family of cysteine proteinases and their protein inhibitors. In: Elödi P (ed) Proteinase action. Akadémiai Kiadó, Budapest, pp 203–217

  3. Brown AL (1987) Positively Darwinian molecules? Nature 326: 12–13

  4. Chandra T, Stackhouse R, Kidd VJ, Robson KJH, Woo SLC (1983) Sequence homology between human α1-antichymotrypsin, α1-antitrypsin and antithrombin III. Biochemistry 22: 5055–5060

  5. Clarke B (1970) Selective constraints on amino-acid substitution during the evolution of proteins. Nature 228:159–160

  6. Creighton TE, Charles IG (1987) Sequences of the genes and polypeptide precursors for two bovine protease inhibitors. J Mol Biol 194:11–22

  7. Dickerson RE, Geis I (1983) Hemoglobin: structure, function, evolution and pathology. Benjamin/Cummings, Menlo Park CA

  8. Fioretti E, Iacopino G, Angeletti M, Barra D, Bossa F, Ascoli F (1985) Primary structure and antiproteolytic activity of a Kunitz-type inhibitor from bovine spleen. J Biol Chem 260: 11451–11455

  9. Gojobori T, Li W-H, Graur D (1982) Patterns of nucleotide substitution in pseudogenes and functional genes. J Mol Evol 18:360–369

  10. Grantham R (1974) Amino acid difference formula to help explain protein evolution. Science 185:862–864

  11. Graur D (1985a) Amino acid composition and the evolutionary rates of protein coding genes. J Mol Evol 22:53–62

  12. Graur D (1985b) Pattern of nucleotide substitution and the extent of purifying selection in retroviruses. J Mol Evol 21: 221–231

  13. Hill RE, Hastie ND (1987) Accelerated evolution in the reactive centre regions of serine protease inhibitors. Nature 326:96–99

  14. Hill RE, Shaw PH, Boyd PA, Baumann H, Hastie ND (1984) Plasma protease inhibitors in mouse and man: divergence within the reactive centre. Nature 311:175–177

  15. Jukes TH, King JL (1971) Deleterious mutations and neutral substitutions. Nature 231:114–115

  16. Kato I, Schrode J, Kohr WJ, Laskowski M (1987) Chicken ovomucoid: determination of its amino acid sequence, determination of the trypsin reactive site, and preparation of all three of its domains. Biochemistry 26:193–201

  17. Kimura M (1968) Evolutionary rate at the molecular level. Nature 217:624–626

  18. Kimura M (1983) The neutral theory of molecular evolution. Cambridge University Press, Cambridge

  19. Klein J, Figueroa F (1986) Evolution of the major histocompatibility complex. CRC Crit Rev Immunol 6:295–386

  20. Laskowski M, Kato I, Ardelt W, Cook J, Denton A, Empie MW, Kohr WJ, Park SJ, Parks K, Schatzley BL, Schoenberger OL, Tashiro M, Vichot G, Whatley HE, Wieczorek A, Wieczorek M (1987a) Ovomucoid third domains from 100 avian species: isolation, sequences, and hypervariability of enzyme-inhibitor contact residues. Biochemistry 26:202–221

  21. Laskowski M, Kato I, Kohr WJ, Park SJ, Tashiro M, Whatley HE (1987b) Positive Darwinian selection in evolution of protein inhibitors of serine proteinases. Cold Spring Harbor Symp Quant Biol 52 (in press)

  22. Li W-H, Wu C-I, Luo C-C (1985) A new method for estimating synonymous and nonsynonymous rates of nucleotide substitution considering the likelihood of nucleotide and codon changes. Mol Biol Evol 2:150–174

  23. Miyata T, Miyazawa S, Yasunaga T (1979) Two types of amino acid substitution in protein evolution. J Mol Evol 12:219–236

  24. Nei M (1975) Molecular population genetics and evolution. North Holland, Amsterdam

  25. Nei M, Graur D (1984) Extent of protein polymorphism and the neutral mutation theory. Evol Biol 17:73–118

  26. Nie NH, Hull CH, Jenkins JG, Steinbrenner K, Bent DH (1975) SPSS. McGraw-Hill, New York

  27. Read RJ, James MNG (1986) Introduction to the protein inhibitors: x-ray crystallography. In: Barrett AJ, Salvesen G (eds) Proteinase inhibitors. Elsevier, Amsterdam, pp 301–336

  28. Schreier PH, Bothwell ALM, Mueller-Hill B, Baltimore D (1981) Multiple differences between the nucleic acid sequence of the IgG2a and IgG2ab alleles of the mouse. Proc Natl Acad Sci USA 78:4495–4499

  29. Shepard HW, Gutman GA (1981) Allelic forms of ratk chain genes: evidence for strong selection at the level of nucleotide sequence. Proc Natl Acad Sci USA 78:7064–7068

  30. Yoon J-B, Towle HC, Seelig S (1987) Growth hormone induces two mRNA species of the serine protease inhibitor gene family in rat liver. J Biol Chem 262:4284–4289

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Correspondence to Dan Graur.

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Graur, D., Li, W. Evolution of protein inhibitors of serine proteinases: Positive Darwinian selection or compositional effects?. J Mol Evol 28, 131–135 (1988). https://doi.org/10.1007/BF02143504

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Key words

  • Rate of amino acid substitutions
  • Amino acid composition
  • Serine proteinase inhibitors
  • Ovomucoids
  • Spi-2
  • Neutral theory
  • Positive Darwinian selection
  • Serpins
  • Kunitz-type inhibitors
  • Kazal-type inhibitors