Search PubMed⌕ Search

Biomedical subjects

N C Franklin

Publications and source records attributed to N C Franklin.

17 recordsLinked to original sources

Clustered arginine residues of bacteriophage lambda N protein are essential to antitermination of transcription, but their locale cannot compensate for boxB loop defects.

The N protein coded by bacteriophage lambda plays an essential role in the completion of lambda transcription by recognizing the boxB sequence in nascent transcripts and then aggregating with Escherichia coli RNA polymerase and four other E. coli proteins into an unstoppable transcription complex. In order to explore the functionality of N protein and the specific recognition between N and boxB, 14 amino acid positions near the amino-terminal end of N lambda were mutated extensively. The mutant proteins were scored for N function in vivo by a two-plasmid construct that visualizes readthrough transcription as lacZ expression in colonies of E. coli. Mutation was achieved by single TAG replacements, translated through suppression into 13 different amino acids, or by scrambling at assorted three-codon sets. Of the 14 amino acid positions tested (Tables 5 and 6), six remained functional with a wide variety of substitutions, while substitution was sometimes deleterious at one Ala and two Gln positions. At each of the five Arg positions, however, maintenance of Arg occupancy proved important for N function. Despite effective screening for increased N function at boxBs with defective loops, no N mutant, simple or complex, was found to change the order of preference of wild-type N lambda for boxBs with defective loops. Thus, although multiple amino-terminal Arg positions are found to be important for N function, mutations in the region spanning the five Arg residues were not found to compensate for defects in boxB loop.

Amino Acid Sequence↗

Effects of all single base substitutions in the loop of boxB on antitermination of transcription by bacteriophage lambda's N protein.

The 'N' antitermination proteins of lambdoid bacteriophages are essential for overcoming multiple transcription terminators located within the major early operons of these phages (1). In order for N proteins to function, a genome sequence specifying N utilization, nut, must be located within an operon, between the promoter and the terminators (2). Two components have been identified within nut: 8-base boxA, conserved among different phages and implicated in the recognition of host NusA protein, required for N function (3); 15-base boxB, an interrupted palindrome (4), diverged in sequence among different lambdoid phages and hypothesized to be the site of recognition for different N proteins, also diverged in sequence (5). Here we apply a plasmid for testing termination and antitermination of transcription (6) to identify mutations at all positions in the 5-7 base loop of lambda's boxB. Almost every base change at any position within the 5-7 base boxB loop was found to constrain antitermination of transcription by the N protein of bacteriophage lambda. These observations extend previous mutational knowledge of nut (7) and are consistant with the hypothesis that the boxB loop is the direct site of recognition for N protein. Variations among the effects of different base changes suggest differential contacts between N protein and bases of the boxB loop, whether in DNA or RNA.

Bacteriophage lambda↗

A plasmid to visualize and assay termination and antitermination of transcription in Escherichia coli.

To facilitate the analysis of termination and antitermination of transcription in prokaryotes, a complex operon has been assembled into the pBR322 replicon, drawing upon natural and synthetic DNA elements. This operon is initiated from a strongly inducible promoter without temperature restraints. It includes a severe transcription terminator and therefore requires antitermination of transcription to express a downstream lacZ reporter gene. Antitermination can be provided by an upstream N-utilization site from phage lambda, working in conjunction with N protein supplied in trans from a compatible plasmid. In this situation, the nusA gene of Salmonella, substituted into the Escherichia coli host, prevents lacZ function, confirming that a good facsimile of lambda's specific antitermination mechanism has been recreated. The nonessential, easily assayed product of this operon, beta-galactosidase, is also screenable by colony color on chromogenic substrate. The plasmid described will therefore serve as a tester for mutations affecting the various aspects of transcription regulation by termination.

Base Sequence↗

Overexpression of N antitermination proteins of bacteriophages lambda, 21, and P22: loss of N protein specificity.

The N protein of bacteriophage lambda (N lambda) modifies Escherichia coli RNA polymerase in such a way that it transcribes through termination signals, a process called antitermination. N antitermination normally occurs only if the template contains a specific utilization or nut site upstream of the terminators and only in the presence of host-encoded Nus proteins. The lambda-related phages 21 and P22 produce N analogs, N21 and N22, but these require different nut sites and show a different pattern of functional interaction with one of the Nus factors, NusA, according to whether this protein is of E. coli or Salmonella origin (NusAEc or NusASal). We report the overproduction of N lambda, N21, or N22, each of which was induced by isopropyl-beta-D-thiogalactopyranoside at 37 degrees C from its cloned position downstream from ptac on a high-expression plasmid, each in a host that provided NusAEc or NusASal. Overproduction of each of these N proteins resulted in relaxed specificity for nut, which was shown by the ability to complement N mutants of heterologous phages; NusA specificity was determined by the N type that was present in these complementation tests. We also observed that excess N was able to suppress transcriptional polarity in the particular case of cloned 'trpA, the last gene of the tryptophan operon, although there was no effect on polarity within chromosomal trpE. Such polarity is attributed to the presence of cryptic intragenic terminators that become exposed in the absence of translation. Because there is no known nut site cis to 'trpA, we suggest that the 'trpA segment itself fortuitously contains a nut sequence that is able to function with excess N of any of the types tested and with either NusAEc or NusASal. We also found that excess N of any specificity, or even inactive N with missense mutation, could cause an increase in the level of NusAEc or NusASal, possibly because interaction between N and NusA, but independent of nut, whether functional or not, interferes with the autoregulation of NusA synthesis. These observations highlight the importance of protein concentration for the specificity of interactions both with other proteins and with nucleic acids. They also indicate that the interaction between N and NusA requires nut participation both for specificity and functionality.

Cloning, Molecular↗

Conservation of genome form but not sequence in the transcription antitermination determinants of bacteriophages lambda, phi 21 and P22.

Comparisons are made among DNA sequences upstream from terminators in both leftwards and rightwards early operons of related coliphages lambda, phi 21 and P22. These sequences include both left and right determinants of response to phage-coded antitermination proteins, "N", as well as the N structural genes themselves. Despite almost total disparity of DNA sequence, the three genomes can be discerned to include the same elements in the same order and spacing: downstream from the early left promoter are sequentially a site of recognition for host nusA protein, a dyad symmetry "nut" essential for N function in lambda, overlapping sites for processing of the transcript by RNAase III and then the N structural genes; downstream from the cro gene on the right are sites of nusA recognition and nut dyad symmetries homologous to those on the left. Because the N proteins of lambda, phi 21 and P22 do not for the most part complement each other, a specific site of N recognition has been postulated for each N-responding operon. The nut dyad symmetry qualifies as such a site, since the loop of the left dyad in lambda is marked by mutations that block N function leftwards, and since DNA sequences here show close homology between the loops of left and right dyads for each phage, but less if not little homology for different phages.

Adult↗

"N" transcription antitermination proteins of bacteriophages lambda, phi 21 and P22.

Comparison is made among the amino acid sequences of three transcription antitermination proteins, based upon the DNA sequences of their genes in bacteriophages lambda, phi 21 and P22. The three proteins are all small (about 100 amino acids), hydrophilic and basic, but otherwise show little homology. A basic region near the amino terminus has several amino acid positions common to all three proteins and is the locus of mutations that alter six different amino acid positions inactivating the lambda N protein. A less basic region near the center is the locus of three mutations affecting the interaction of lambda N with host nusA protein. The N gene of phi 21 has an amino terminus more like that of P22, and a carboxy terminus clearly related to that of lambda.

Amino Acid Sequence↗

The N protein of bacteriophage lambda, defined by its DNA sequence, is highly basic.

Nucleotide sequence has been determined for the restriction fragments and cloned DNA from the pL-N-tL1 region of bacteriophage lambda. A unique reading frame for the N gene is defined by the absence of natural nonsense codons and by the presence of seven nonsense codons generated by mutations in N. This reading frame is initiated at two alternative ATG codons, the second of which is probably the in vivo translation start. Reading is stopped at a single TAG codon. The protein coded is therefore 133 or, more probably, 107 amino acids long, rich in lysine, arginine and proline.

Bacteriophage lambda↗