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The Lon AAA+ Protease

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Regulated Proteolysis in Microorganisms

Part of the book series: Subcellular Biochemistry ((SCBI,volume 66))

Abstract

As the first ATP-dependent protease to be identified, Lon holds a special place in the history of cellular biology. In fact, the concept of ATP-dependent protein degradation was established through the findings that led to the discovery of Lon. Therefore, this chapter begins with a historical perspective, describing the milestones that led to the discovery of Lon and ATP-dependent proteolysis, starting from the early findings in the 1960s until the demonstration of Lon’s ATP-dependent proteolytic activity in vitro, in 1981. Most of our knowledge on Lon derives from studies of the Escherichia coli Lon ortholog, and, therefore, most of this chapter relates to this particular enzyme. Nonetheless, Lon is not only found in most bacterial species, it is also found in Archaea and in the mitochondrion and chloroplast of eukaryotic cells. Therefore many of the conclusions gained from studies on the E. coli enzyme are relevant to Lon proteases in other organisms. Lon, more than any other bacterial or organellar protease, is associated with the degradation of misfolded proteins and protein quality control. In addition, Lon also degrades many regulatory proteins that are natively folded, thus it also plays a prominent role in regulation of physiological processes. Throughout the years, many Lon substrates have been identified, confirming its role in the regulation of diverse cellular processes, including cell division, DNA replication, differentiation, and adaptation to stress conditions. Some examples of these functions are described and discussed here, as is the role of Lon in the degradation of misfolded proteins and in protein quality control. Finally, this chapter deals with the exquisite sensitivity of protein degradation inside a cell. How can a protease distinguish so many substrates from cellular proteins that should not be degraded? Can the specificity of a protease be regulated according to the physiological needs of a cell? This chapter thus broadly discusses the substrate specificity of Lon and its allosteric regulation.

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References

  1. Jacob F, Monod J (1961) Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 3:318–356

    Article  PubMed  CAS  Google Scholar 

  2. Markovitz A (1964) Regulatory mechanisms for synthesis of capsular polysaccharide in mucoid mutants of Escherichia coli K12. Proc Natl Acad Sci U S A 51:239–246

    Article  PubMed  CAS  Google Scholar 

  3. Adler HI, Hardigree AA (1964) Cell elongation in strains of Escherichia coli. J Bacteriol 87(5):1240–1242

    PubMed  CAS  Google Scholar 

  4. Adler HI, Hardigree AA (1964) Analysis of a gene controlling cell division and sensitivity to radiation in Escherichia coli. J Bacteriol 87:720–726

    PubMed  CAS  Google Scholar 

  5. Howard-Flanders P, Simson E, Theriot L (1964) A locus that controls filament formation and sensitivity to radiation in Escherichia coli K-12. Genetics 49:237–246

    PubMed  CAS  Google Scholar 

  6. Bush JW, Markovitz A (1973) The genetic basis for mucoidy and radiation sensitivity in capR (lon) mutants of E. coli K-12. Genetics 74(2):215–225

    PubMed  CAS  Google Scholar 

  7. Zehnbauer BA, Foley EC, Henderson GW, Markovitz A (1981) Identification and purification of the Lon+(capR+) gene product, a DNA-binding protein. Proc Natl Acad Sci U S A 78(4):2043–2047

    Article  PubMed  CAS  Google Scholar 

  8. Newton WA, Beckwith JR, Zipser D, Brenner S (1965) Nonsense mutants and polarity in the lac operon of Escherichia coli. J Mol Biol 14(1):290–296

    Article  PubMed  CAS  Google Scholar 

  9. Morrison SL, Zipser D (1970) Polypeptide products of nonsense mutations. I. Termination fragments from nonsense mutations in the Z gene of the lac operon of Escherichia coli. J Mol Biol 50(2):359–371

    Article  PubMed  CAS  Google Scholar 

  10. Morrison SL, Zipser D, Goldschmidt R (1971) Polypeptide products of nonsense mutations. II. Minor fragments produced by nonsense mutations in the z gene of the lactose operon of Escherichia coli. J Mol Biol 60(3):485–497

    Article  PubMed  CAS  Google Scholar 

  11. Goldschmidt R (1970) In vivo degradation of nonsense fragments in E. coli. Nature 228(5277):1151–1154

    Article  PubMed  CAS  Google Scholar 

  12. Goldberg AL (1972) Degradation of abnormal proteins in Escherichia coli (protein breakdown-protein structure-mistranslation-amino acid analogs-puromycin). Proc Natl Acad Sci U S A 69(2):422–426

    Article  PubMed  CAS  Google Scholar 

  13. Platt T, Miller JH, Weber K (1970) In vivo degradation of mutant lac repressor. Nature 228(5277):1154–1156

    Article  PubMed  CAS  Google Scholar 

  14. Bukhari AI, Zipser D (1973) Mutants of Escherichia coli with a defect in the degradation of nonsense fragments. Nat New Biol 243(129):238–241

    PubMed  CAS  Google Scholar 

  15. Ullmann A, Jacob F, Monod J (1967) Characterization by in vitro complementation of a peptide corresponding to an operator-proximal segment of the beta-galactosidase structural gene of Escherichia coli. J Mol Biol 24(2):339–343

    Article  PubMed  CAS  Google Scholar 

  16. Gottesman S, Zipser D (1978) Deg phenotype of Escherichia coli lon mutants. J Bacteriol 133(2):844–851

    PubMed  CAS  Google Scholar 

  17. Etlinger JD, Goldberg AL (1977) A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes. Proc Natl Acad Sci U S A 74(1):54–58

    Article  PubMed  CAS  Google Scholar 

  18. Goldberg AL, Strnad NP, Swamy KH (1979) Studies of the ATP dependence of protein degradation in cells and cell extracts. CIBA Found Symp 75:227–251

    PubMed  Google Scholar 

  19. Murakami K, Voellmy R, Goldberg AL (1979) Protein degradation is stimulated by ATP in extracts of Escherichia coli. J Biol Chem 254(17):8194–8200

    PubMed  CAS  Google Scholar 

  20. Swamy KH, Goldberg AL (1981) E. coli contains eight soluble proteolytic activities, one being ATP dependent. Nature 292(5824):652–654

    Article  PubMed  CAS  Google Scholar 

  21. Chung CH, Goldberg AL (1981) The product of the lon (capR) gene in Escherichia coli is the ATP-dependent protease, protease La. Proc Natl Acad Sci U S A 78(8):4931–4935

    Article  PubMed  CAS  Google Scholar 

  22. Charette MF, Henderson GW, Markovitz A (1981) ATP hydrolysis-dependent protease activity of the lon (capR) protein of Escherichia coli K-12. Proc Natl Acad Sci U S A 78(8):4728–4732

    Article  PubMed  CAS  Google Scholar 

  23. Gottesman S, Trisler P, Torres-Cabassa A (1985) Regulation of capsular polysaccharide synthesis in Escherichia coli K-12: characterization of three regulatory genes. J Bacteriol 162(3):1111–1119

    PubMed  CAS  Google Scholar 

  24. Torres-Cabassa AS, Gottesman S (1987) Capsule synthesis in Escherichia coli K-12 is regulated by proteolysis. J Bacteriol 169(3):981–989

    PubMed  CAS  Google Scholar 

  25. Donch J, Chung YS, Greenberg J (1969) Locus for radiation resistance in Escherichia coli strain B-r. Genetics 61(2):363–370

    PubMed  CAS  Google Scholar 

  26. Johnson BF, Greenberg J (1975) Mapping of sul, the suppressor of lon in Escherichia coli. J Bacteriol 122(2):570–574

    PubMed  CAS  Google Scholar 

  27. Gottesman S, Halpern E, Trisler P (1981) Role of sulA and sulB in filamentation by lon mutants of Escherichia coli K-12. J Bacteriol 148(1):265–273

    PubMed  CAS  Google Scholar 

  28. Mizusawa S, Gottesman S (1983) Protein degradation in Escherichia coli: the lon gene controls the stability of sulA protein. Proc Natl Acad Sci U S A 80(2):358–362

    Article  PubMed  CAS  Google Scholar 

  29. Butala M, Zgur-Bertok D, Busby SJ (2009) The bacterial LexA transcriptional repressor. Cell Mol Life Sci 66(1):82–93

    Article  CAS  Google Scholar 

  30. d’Ari R (1985) The SOS system. Biochimie 67(3–4):343–347

    Article  PubMed  Google Scholar 

  31. Sutton MD, Smith BT, Godoy VG, Walker GC (2000) The SOS response: recent insights into umuDC-dependent mutagenesis and DNA damage tolerance. Annu Rev Genet 34:479–497

    Article  PubMed  CAS  Google Scholar 

  32. Bi E, Lutkenhaus J (1993) Cell division inhibitors SulA and MinCD prevent formation of the FtsZ ring. J Bacteriol 175(4):1118–1125

    PubMed  CAS  Google Scholar 

  33. Cordell SC, Robinson EJ, Lowe J (2003) Crystal structure of the SOS cell division inhibitor SulA and in complex with FtsZ. Proc Natl Acad Sci U S A 100(13):7889–7894

    Article  PubMed  CAS  Google Scholar 

  34. Tsilibaris V, Maenhaut-Michel G, Van Melderen L (2006) Biological roles of the Lon ATP-dependent protease. Res Microbiol 157(8):701–713

    Article  PubMed  CAS  Google Scholar 

  35. Barchinger SE, Ades SE (2013) Regulated proteolysis: control of the Escherichia coli σE-dependent cell envelope stress response. In: Dougan DA (ed) Regulated proteolysis in microorganisms. Springer, Subcell Biochem 66:129–160

    Google Scholar 

  36. Frees D, Brøndsted L, Ingmer H (2013) Bacterial proteases and virulence. In: Dougan DA (ed) Regulated proteolysis in microorganisms. Springer, Subcell Biochem 66:161–192

    Google Scholar 

  37. Molière N, Turgay K (2013) General and regulatory proteolysis in Bacillus subtilis. In: Dougan DA (ed) Regulated proteolysis in microorganisms. Springer, Subcell Biochem 66:73–103

    Google Scholar 

  38. Birghan C, Mundt E, Gorbalenya AE (2000) A non-canonical lon proteinase lacking the ATPase domain employs the ser-Lys catalytic dyad to exercise broad control over the life cycle of a double-stranded RNA virus. EMBO J 19(1):114–123

    Article  PubMed  CAS  Google Scholar 

  39. Botos I, Melnikov EE, Cherry S, Tropea JE et al (2004) The catalytic domain of Escherichia coli Lon protease has a unique fold and a Ser-Lys dyad in the active site. J Biol Chem 279(9):8140–8148

    Article  PubMed  CAS  Google Scholar 

  40. Polgar L (2005) The catalytic triad of serine peptidases. Cell Mol Life Sci 62(19–20):2161–2172

    Article  CAS  Google Scholar 

  41. Rotanova TV, Melnikov EE, Khalatova AG, Makhovskaya OV et al (2004) Classification of ATP-dependent proteases Lon and comparison of the active sites of their proteolytic domains. Eur J Biochem 271(23–24):4865–4871

    Article  CAS  Google Scholar 

  42. Cha SS, An YJ, Lee CR, Lee HS et al (2010) Crystal structure of Lon protease: molecular architecture of gated entry to a sequestered degradation chamber. EMBO J 29(20):3520–3530

    Article  PubMed  CAS  Google Scholar 

  43. Stahlberg H, Kutejova E, Suda K, Wolpensinger B et al (1999) Mitochondrial Lon of Saccharomyces cerevisiae is a ring-shaped protease with seven flexible subunits. Proc Natl Acad Sci U S A 96(12):6787–6790

    Article  PubMed  CAS  Google Scholar 

  44. Vale RD (2000) AAA proteins. Lords of the ring. J Cell Biol 150(1):F13–F19

    Article  PubMed  CAS  Google Scholar 

  45. Rudyak SG, Brenowitz M, Shrader TE (2001) Mg2  +  −linked oligomerization modulates the catalytic activity of the Lon (La) protease from Mycobacterium smegmatis. Biochemistry 40(31):9317–9323

    Article  PubMed  CAS  Google Scholar 

  46. Park SC, Jia B, Yang JK, Van DL et al (2006) Oligomeric structure of the ATP-dependent protease La (Lon) of Escherichia coli. Mol Cells 21(1):129–134

    PubMed  CAS  Google Scholar 

  47. Sousa MC, Trame CB, Tsuruta H, Wilbanks SM et al (2000) Crystal and solution structures of an HslUV protease-chaperone complex. Cell 103(4):633–643

    Article  PubMed  CAS  Google Scholar 

  48. Wang J, Hartling JA, Flanagan JM (1997) The structure of ClpP at 2.3 A resolution suggests a model for ATP-dependent proteolysis. Cell 91(4):447–456

    Article  PubMed  CAS  Google Scholar 

  49. Botos I, Melnikov EE, Cherry S, Kozlov S et al (2005) Atomic-resolution crystal structure of the proteolytic domain of Archaeoglobus fulgidus lon reveals the conformational variability in the active sites of lon proteases. J Mol Biol 351(1):144–157

    Article  PubMed  CAS  Google Scholar 

  50. Im YJ, Na Y, Kang GB, Rho SH et al (2004) The active site of a lon protease from Methanococcus jannaschii distinctly differs from the canonical catalytic Dyad of Lon proteases. J Biol Chem 279(51):53451–53457

    Article  PubMed  CAS  Google Scholar 

  51. Botos I, Melnikov EE, Cherry S, Khalatova AG (2004) Crystal structure of the AAA  +  alpha domain of E. coli Lon protease at 1.9A resolution. J Struct Biol 146(1–2):113–122

    Article  PubMed  CAS  Google Scholar 

  52. Li M, Rasulova F, Melnikov EE, Rotanova TV (2005) Crystal structure of the N-terminal domain of E. coli Lon protease. Protein Sci 14(11):2895–2900

    Article  CAS  Google Scholar 

  53. Duman RE, Lowe J (2010) Crystal structures of Bacillus subtilis Lon protease. J Mol Biol 401(4):653–670

    Article  PubMed  CAS  Google Scholar 

  54. Gur E, Ottofuelling R, Dougan DA (2013) Machines of destruction: AAA+ proteases and the adaptors that control them. In: Dougan DA (ed) Regulated proteolysis in microorganisms. Springer, Subcell Biochem 66:3–33

    Google Scholar 

  55. Vineyard D, Patterson-Ward J, Lee I (2006) Single-turnover kinetic experiments confirm the existence of high- and low-affinity ATPase sites in Escherichia coli Lon protease. Biochemistry 45(14):4602–4610

    Article  PubMed  CAS  Google Scholar 

  56. Glynn SE, Martin A, Nager AR, Baker TA et al (2009) Structures of asymmetric ClpX hexamers reveal nucleotide-dependent motions in a AAA  +  protein-unfolding machine. Cell 139(4):744–756

    Article  PubMed  CAS  Google Scholar 

  57. Hersch GL, Burton RE, Bolon DN, Baker TA et al (2005) Asymmetric interactions of ATP with the AAA  +  ClpX6 unfoldase: allosteric control of a protein machine. Cell 121(7):1017–1027

    Article  PubMed  CAS  Google Scholar 

  58. Yakamavich JA, Baker TA, Sauer RT (2008) Asymmetric nucleotide transactions of the HslUV protease. J Mol Biol 380(5):946–957

    Article  PubMed  CAS  Google Scholar 

  59. Roudiak SG, Shrader TE (1998) Functional role of the N-terminal region of the Lon protease from Mycobacterium smegmatis. Biochemistry 37(32):11255–11263

    Article  PubMed  CAS  Google Scholar 

  60. Celis JE, Smith JD, Brenner S (1973) Correlation between genetic and translational maps of gene 23 in bacteriophage T4. Nat New Biol 241(109):130–132

    PubMed  CAS  Google Scholar 

  61. Simon LD, Tomczak K, St John AC (1978) Bacteriophages inhibit degradation of abnormal proteins in E. coli. Nature 275(5679):424–428

    Article  PubMed  CAS  Google Scholar 

  62. Skorupski K, Tomaschewski J, Ruger W, Simon LD (1988) A bacteriophage T4 gene which functions to inhibit Escherichia coli Lon protease. J Bacteriol 170(7):3016–3024

    PubMed  CAS  Google Scholar 

  63. Hilliard JJ, Maurizi MR, Simon LD (1998) Isolation and characterization of the phage T4 PinA protein, an inhibitor of the ATP-dependent lon protease of Escherichia coli. J Biol Chem 273(1):518–523

    Article  PubMed  CAS  Google Scholar 

  64. Hilliard JJ, Simon LD, Van Melderen L, Maurizi MR (1998) PinA inhibits ATP hydrolysis and energy-dependent protein degradation by Lon protease. J Biol Chem 273(1):524–527

    Article  PubMed  CAS  Google Scholar 

  65. Mogk A, Huber D, Bukau B (2011) Integrating protein homeostasis strategies in prokaryotes. Cold Spring Harb Perspect Biol 3(4)

    Google Scholar 

  66. Gur E, Sauer RT (2008) Recognition of misfolded proteins by Lon, a AAA(+) protease. Genes Dev 22(16):2267–2277

    Article  PubMed  CAS  Google Scholar 

  67. Ishii Y, Sonezaki S, Iwasaki Y, Miyata Y et al (2000) Regulatory role of C-terminal residues of SulA in its degradation by Lon protease in Escherichia coli. J Biochem 127(5):837–844

    Article  PubMed  CAS  Google Scholar 

  68. Gur E, Sauer RT (2009) Degrons in protein substrates program the speed and operating efficiency of the AAA + Lon proteolytic machine. Proc Natl Acad Sci U S A 106(44):18503–18508

    Article  PubMed  CAS  Google Scholar 

  69. Ishii Y, Amano F (2001) Regulation of SulA cleavage by Lon protease by the C-terminal amino acid of SulA, histidine. Biochem J 358(Pt 2):473–480

    Article  PubMed  CAS  Google Scholar 

  70. Monod J, Wyman J, Changeux JP (1965) On the nature of allosteric transitions: a plausible model. J Mol Biol 12:88–118

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Life Sciences Department, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel

    Eyal Gur

  2. Life Sciences Department, The National Institute for Biotechnology in the Negev, Beer-Sheva, 84105, Israel

    Eyal Gur

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  1. Eyal Gur
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Correspondence to Eyal Gur .

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  1. , Department of Biochemistry, La Trobe Institute for Molecular Science, Plenty Rd, Melbourne, 3086, Victoria, Australia

    David A. Dougan

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Gur, E. (2013). The Lon AAA+ Protease. In: Dougan, D. (eds) Regulated Proteolysis in Microorganisms. Subcellular Biochemistry, vol 66. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5940-4_2

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