Production of recombinant thermostable proteins expressed in Escherichia coli: completion of protein synthesis is the bottleneck

J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Mar 25;786(1-2):207-14. doi: 10.1016/s1570-0232(02)00689-x.

Abstract

Heterologous expression and high yield purification of proteins are frequently required for structural and functional investigations. Purification of recombinant thermostable proteins is essentially trivial since unwanted mesophilic host protein can efficiently be removed by heat denaturation. However, heterologous expression in E. coli often results in truncated protein forms. In many cases, this is a consequence of abundant codons in heterologous genes, which are decoded by rare tRNAs in E. coli-a combination that can be responsible for translational stalling and termination during protein biosynthesis. Other complications may originate from potential initiation codons and ribosomal binding sites present inside the open reading frame of the target gene or from other less well defined phenomena such as mRNA instability. Separation of full-length protein from truncated forms is a serious chromatographic problem that can be solved in the expression step. We have investigated the heterologous expression and purification of two translation initiation factors from the hyperthermophilic sulphate-reducing archaeon, Archaeoglobus fulgidus. Expression in E. coli was optimised to avoid truncated forms completely by complementation with the plasmids pSJS1244, pRIG, pCODON+ and pLysSR.A.R.E harbouring and expressing genes encoding rare tRNAs corresponding to the codons AGA, AGG, AUA, CUA, GGA, AAG and CCC. Two expression strains, C41(DE3) and C43(DE3) were found highly advantageous when combined with rare tRNA encoding plasmids as compared to BL21(DE3). We have also investigated the effects of site directed mutagenesis on rare lysine encoding AAG doublets as well as two methionine residues preceded by potential ribosomal binding sites. The expression approach presented here has enabled us to purify gram quantities of full-length protein by one step of ion-exchange chromatography and is generally applicable to many other heterologously expressed thermostable proteins.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • DNA Primers
  • DNA, Recombinant
  • Electrophoresis, Polyacrylamide Gel
  • Escherichia coli / genetics*
  • Molecular Sequence Data
  • Recombinant Proteins / biosynthesis*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification

Substances

  • DNA Primers
  • DNA, Recombinant
  • Recombinant Proteins