DnaG

Last updated
DNA primase
Identifiers
Organism E. coli K-12 substr. MG1655, Bacillus stearothermophilus
SymboldnaG
Alt. symbolsdnaP
Entrez 947570
PDB 1D0Q, 1DD9, 1DDE, 1EQ9, 2R6A, 2R6C
RefSeq (Prot) NP_417538
UniProt P0ABS5
Other data
EC number 2.7.7.7
Chromosome chromosome: 3.21 - 3.21 Mb
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Structures Swiss-model
Domains InterPro

DnaG is a bacterial DNA primase and is encoded by the dnaG gene. The enzyme DnaG, and any other DNA primase, synthesizes short strands of RNA known as oligonucleotides during DNA replication. These oligonucleotides are known as primers because they act as a starting point for DNA synthesis. DnaG catalyzes the synthesis of oligonucleotides that are 10 to 60 nucleotides (the fundamental unit of DNA and RNA) long, however most of the oligonucleotides synthesized are 11 nucleotides. [1] These RNA oligonucleotides serve as primers, or starting points, for DNA synthesis by bacterial DNA polymerase III (Pol III). DnaG is important in bacterial DNA replication because DNA polymerase cannot initiate the synthesis of a DNA strand, but can only add nucleotides to a preexisting strand. [2] DnaG synthesizes a single RNA primer at the origin of replication. This primer serves to prime leading strand DNA synthesis. For the other parental strand, the lagging strand, DnaG synthesizes an RNA primer every few kilobases (kb). These primers serve as substrates for the synthesis of Okazaki fragments. [3]

Contents

In E. coli DnaG associates through noncovalent interactions with bacterial replicative helicase DnaB to perform its primase activity, with three DnaG primase proteins associating with each DnaB helicase to form the primosome. [4] Primases tend to initiate synthesis at specific three nucleotide sequences on single-stranded DNA (ssDNA) templates and for E. coli DnaG the sequence is 5'-CTG-3'. [1]

DnaG contains three separate protein domains: a zinc binding domain, an RNA polymerase domain, and a DnaB helicase binding domain. There are several bacteria that use the DNA primase DnaG. A few organisms that have DnaG as their DNA primase are Escherichia coli (E. coli), Bacillus stearothermophilus , and Mycobacterium tuberculosis (MTB). E. coli DnaG has a molecular weight of 60 kilodaltons (kDa) and contains 581 amino acids.

Function

DnaG (DNA primase) is an essential enzyme involved in the DNA replication fork DNA replication en.svg
DnaG (DNA primase) is an essential enzyme involved in the DNA replication fork
Organic mechanism of oligonucleotide synthesis of ribonucleic acid (RNA) in the 5' to 3' direction Oligonucleotide Synthesis3.jpg
Organic mechanism of oligonucleotide synthesis of ribonucleic acid (RNA) in the 5' to 3' direction

DnaG catalyzes the synthesis of oligonucleotides in five discrete steps: template binding, nucleoside triphosphate (NTP) binding, initiation, extension to form a primer, and primer transfer to DNA polymerase III. [1] DnaG performs this catalysis near the replication fork that is formed by DnaB helicase during DNA replication. DnaG must be complexed with DnaB in order for it to catalyze the formation of the oligonucleotide primers. [1]

The mechanism for primer synthesis by primases involves two NTP binding sites on the primase protein (DnaG). [5] Prior to the binding of any NTPs to form the RNA primer, the ssDNA template sequence binds to DnaG. The ssDNA contains a three nucleotide recognition sequence that recruits NTPs based on Watson-Crick base pairing. [1] After binding DNA, DnaG must bind two NTPs in order to generate an enzyme-DNA-NTP-NTP quaternary complex. The Michaelis constant's (km) for the NTPs vary depending on the primase and templates. [6] The two NTP binding sites on DnaG are referred to as the initiation site and elongation site. The initiation site is the site at which the NTP to be incorporated at the 5' end of the primer binds. The elongation site binds the NTP that is added to the 3' end of the primer.

Once two nucleotides are bound to the primase, DnaG catalyzes the formation of a dinucleotide by forming a phosphodiester bond via dehydration synthesis between the 3' hydroxyl of the nucleotide in the initiation site and the α-phosphate of the nucleotide in the elongation site. This reaction results in a dinucleotide and breaking of the bond between the α and β phosphorus, releasing pyrophosphate. This reaction is irreversible because the pyrophosphate that is formed is hydrolyzed into two inorganic phosphate molecules by the enzyme inorganic pyrophosphatase. [7] This dinucleotide synthesis reaction is the same reaction as any other enzyme that catalyzes the formation of DNA or RNA (DNA Polymerase, RNA Polymerase), therefore DnaG must always synthesize oligonucleotides in the 5' to 3' direction. In E. coli, primers begin with a triphosphate adenine-guanine (pppAG) dinucleotide at the 5' end.

In order for further elongation of the dinucleotide to occur, oligonucleotide must be moved so that the 3' NTP is transferred from the elongation site to the initiation site, allowing for another NTP to bind to the elongation site and attach to the 3' hydroxyl of the oligonucleotide. Once an oligonucleotide of appropriate length has been synthesized from the elongation step of primer synthesis, DnaG transfers the newly synthesized primer to DNA polymerase III for it to synthesize the DNA leading strand or Okazaki fragments for the lagging strand. [1] The rate limiting step of the primer synthesis occurs after NTP binding but before or during dinucleotide synthesis. [6]

Structure

The E. Coli DnaG primase is a 581 residue monomeric protein with three functional domains, according to proteolysis studies. There is an N-terminal Zinc-binding domain (residues 1–110) where a zinc ion is tetrahedrally coordinated between one histidine and three cysteine residues, which plays a role in recognizing sequence specific DNA binding sites. The central domain (residues 111–433) displays RNA polymerase activities, and is the site of RNA primer synthesis. The C-terminal domain (residues 434–581) is responsible for the noncovalent binding of DnaG to the DnaB helicase protein. [8]

Zinc-Binding Domain

Left: The structure of Bacillus stearothermophilus zinc-binding domain, with the conserved hydrophobic and basic residues shown in silver.Right: Enlarged image of the zinc-binding site showing Cys40, Cys61, Cys64 and His43 coordinating a zinc ion. Diagram rendered from PDB 1D0Q. DnaG Zinc Binding Domain.png
Left: The structure of Bacillus stearothermophilus zinc-binding domain, with the conserved hydrophobic and basic residues shown in silver.Right: Enlarged image of the zinc-binding site showing Cys40, Cys61, Cys64 and His43 coordinating a zinc ion. Diagram rendered from PDB 1D0Q.

The zinc-binding domain, the domain responsible for recognizing sequence specific DNA binding sites, is conserved across all viral, bacteriophage, prokaryotic and eukaryotic DNA primases. [9] The primase zinc-binding domain is part of the subfamily of zinc-binding domains known as the zinc ribbon. Zinc ribbon domains are characterized by two β-hairpin loops which form the zinc-binding domain. Typically, zinc ribbon domains are thought to lack α-helices, distinguishing them from other zinc-binding domains. However, in 2000 DnaG's zinc-binding domain was crystallized from Bacillus stearothermophilus revealing that the domain consisted of a five stranded antiparallel β sheet adjacent to four α helices and a 310 helix on the c-terminal end of the domain. [9]

The zinc-binding site of B. stearothermophilus consists of three cysteine residues, Cys40, Cys61, and Cys64, and one histidine residue, His43. Cys40 and His43 are located on the β-hairpin between the second and third β sheet. [9] Cys61 is located on the fifth β sheet, and Cys64 is on the β-hairpin between the fourth and fifth β sheet. These four residues coordinate the zinc ion tetrahedrally. The zinc ion is thought to stabilize the loops between the second and third β sheet as well as the fourth and fifth β sheet. The domain is further stabilized by a number of hydrophobic interactions between the hydrophobic inner surface of the β sheet which is packed against the second and third α helices. The outer surface of the β sheet also has many conserved hydrophobic and basic residues. These residues are Lys30, Arg34, Lys46, Pro48, Lys56, Ile58, His60 and Phe62. [9]

DNA Binding

It is thought that the function of the zinc binding domain is for sequence specific DNA recognition. DNA primases make RNA primers which are then used for DNA synthesis. The placement of the RNA primers is not random, suggesting that they are placed on specific DNA sequences. Indeed, other DNA primases have been shown to recognize triplet sequences; the specific sequence recognized by B. stearothermophilus has not yet been identified. [9] It has been shown that if the cystine residues that coordinate the zinc ion are mutated, the DNA primase stops functioning. This indicates that the zinc-binding domain does play a role in sequence recognition. In addition, the hydrophobic surface of the β sheet, as well as the basic residues which are clustered primarily on one edge of the sheet, serve to attract single stranded DNA, further facilitating DNA binding. [9]

Based on previous studies of DNA binding by DNA Primases, it is thought that DNA binds to the zinc-binding domain across the surface of the β sheet, with the three nucleotides binding across three strands of the β sheet. [9] The positively charged residues in the sheet would be able to form contacts with the phosphates and the aromatic residues would form stacking interactions with the bases. This is the model of DNA binding by the ssDNA-binding domain of replication protein A (RPA). [9] It is logical to assume that B. stearothermophilus’ zinc-binding domain binds DNA in a similar manner, as the residues important for binding DNA in RPA occur in structurally equivalent positions in B. stearothermophilus. [9]

RNA Polymerase Domain

Structure of E. coli's DnaG RNA Polymerase Domain. The highly conserved basic residues, Arg146, Arg221, and Lys229 are shown in yellow. This image was rendered from PDB 1DD9. DnaG RNA Polymerase Domain.png
Structure of E. coli's DnaG RNA Polymerase Domain. The highly conserved basic residues, Arg146, Arg221, and Lys229 are shown in yellow. This image was rendered from PDB 1DD9.

As its name suggests, the RNA polymerase domain (RNAP) of DnaG is responsible for synthesizing the RNA primers on the single stranded DNA. In-vivo, DnaG is able to synthesis primer fragments of up to 60 nucleotides, but in-vivo primer fragments are limited to approximately 11 nucleotides. [10] During the synthesis of the lagging strand DnaG synthesizes between 2000 and 3000 primers at a rate of one primer per-second. [10]

RNAP domain of DnaG has three subdomains, the N-terminal domain, which has a mixed α and β fold, the central domain consisting of a 5 stranded β sheet and 6 α helices, and finally the C-terminal domain which is made up of a helical bundle consisting of 3 antiparallel α helices. The central domain is made up in part of the toprim fold, a fold that has been observed in many metal-binding phosphotransfer proteins. The central domain and the N-terminal domain form a shallow cleft, which makes up the active site of the RNA chain elongation in DnaG. [10] The opening of the cleft is lined by several highly conserved basic residues: Arg146, Arg221, and Lys229. These residues are part of the electrostatically positive ridge of the N-terminal subdomain. It is this ridge that interacts with the ssDNA and helps guide it into the cleft, which consists of the metal binding center of the toprim motif on the central subdomain, and the conserved primase motifs of the N-terminal domain. [10] The metal binding site of the toprim domain is where the primer is synthesized. The RNA:DNA duplex then exits through another basic depression.

C-Terminal Domain

The structure of E. Coli's helicase binding domain. Rendered from PDB 2R6A. The lower two helices form the helical hairpin of the C2 subdomain. The remaining five helices form the helical bundle of the C1 subdomain. Helicase Binding Domain of E. Coli.JPG
The structure of E. Coli's helicase binding domain. Rendered from PDB 2R6A. The lower two helices form the helical hairpin of the C2 subdomain. The remaining five helices form the helical bundle of the C1 subdomain.

Unlike both the zinc-binding domains, and the RNA polymerase domains, the C-terminal domains of DNA primases are not conserved. In prokaryotic primases, the only known function of this domain is to interact with the helicase, DnaB. [1] Thus, this domain is called the helicase binding domain (HBD). The HBD of DnaG consists of two subdomains: a helical bundle, the C1 subdomain, and a helical hairpin, the C2 subdomain. [4] [11] For each of the two to three DnaG molecules that bind the DnaB hexamer, the C1 subdomains of the HBDs interact with DnaB at its N-terminal domains on the inner surface of the hexamer ring, while the C2 subdomains interact with the N-terminal domains on the outer surface of the hexamer.

Bacillus stearothermophilus DnaG, blue, in complex with the hexameric DnaB, green. Rendered from PDB 2R6A Bacillus stearothermophilus DnaG in compex with the hexameric DnaB..JPG
Bacillus stearothermophilus DnaG, blue, in complex with the hexameric DnaB, green. Rendered from PDB 2R6A

Three residues in B. stearothermophilus DnaB have been identified as important for formation of the DnaB, DnaG interface. Those residues include Tyr88, Ile119, and Ile125. [4] Tyr88 is close in proximity to, but does not make contact with, the HBD of DnaG. Mutation of Tyr88 inhibits the formation of the N-terminal domain helical bundle of DnaB, interrupting the contacts with the HBD of DnaG. [4] The hexameric structure of DnaB is really a trimer of dimers. Both Ile119 and Ile125 are buried in the N-terminal domain dimer interface of DnaB and mutation of these residues inhibits formation of the hexameric structure and thus the interaction with DnaG. [4] One other residue that has been identified as playing a crucial role in the interaction of DnaB and DnaG is Glu15. Mutation of Glu15 does not disrupt the formation of the DnaB, DnaG complex, but instead plays a role in modulating the length of primers synthesized by DnaG. [4]

Inhibition of DnaG

NTP analogs that are known to inhibit DnaG as well as other polymerase enzymes Inhibitor Structures.jpg
NTP analogs that are known to inhibit DnaG as well as other polymerase enzymes

Inhibitors of DNA primases are valuable compounds for the elucidation of biochemical pathways and key interactions, but they are also of interest as lead compounds to design drugs against bacterial diseases. Most of the compounds known to inhibit primases are nucleotide analogs such as AraATP (see Vidarabine) and 2-fluoro-AraATP. These compounds will often be used as substrates by the primase, but once incorporated synthesis or elongation can no longer occur. For example, E. coli DnaG will use 2',3'-dideoxynucleoside 5'-triphosphates (ddNTPs) as substrates, which act as chain terminators due to the lack of a 3' hydroxyl to form a phosphodiester bond with the next nucleotide. [1]

The relatively small number of primase inhibitors likely reflects the inherent difficulty of primase assays rather than a lack of potential binding sites on the enzyme. The short length of products synthesized and the generally slow rate of the enzyme compared to other replication enzymes make developing high-throughput screening (HTS) approaches more difficult. [6] Despite the difficulties, there are several known inhibitors of DnaG that are not NTP analogues. Doxorubicin and suramin are both DNA and NTP competitive inhibitors of Mycobacterium Tuberculosis DnaG. [12] Suramin is also known to inhibit eukaryotic DNA primase by competing with GTP, so suramin is likely to inhibit DnaG via a similar mechanism. [1]

Related Research Articles

<span class="mw-page-title-main">DNA replication</span> Biological process

In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part of biological inheritance. This is essential for cell division during growth and repair of damaged tissues, while it also ensures that each of the new cells receives its own copy of the DNA. The cell possesses the distinctive property of division, which makes replication of DNA essential.

<span class="mw-page-title-main">Polymerase</span> Class of enzymes which synthesize nucleic acid chains or polymers

In biochemistry, a polymerase is an enzyme that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by copying a DNA template strand using base-pairing interactions or RNA by half ladder replication.

<span class="mw-page-title-main">Primer (molecular biology)</span> Short strand of RNA or DNA that serves as a starting point for DNA synthesis

A primer is a short, single-stranded nucleic acid used by all living organisms in the initiation of DNA synthesis. A synthetic primer may also be referred to as an oligo, short for oligonucleotide. DNA polymerase enzymes are only capable of adding nucleotides to the 3’-end of an existing nucleic acid, requiring a primer be bound to the template before DNA polymerase can begin a complementary strand. DNA polymerase adds nucleotides after binding to the RNA primer and synthesizes the whole strand. Later, the RNA strands must be removed accurately and replace them with DNA nucleotides forming a gap region known as a nick that is filled in using an enzyme called ligase. The removal process of the RNA primer requires several enzymes, such as Fen1, Lig1, and others that work in coordination with DNA polymerase, to ensure the removal of the RNA nucleotides and the addition of DNA nucleotides. Living organisms use solely RNA primers, while laboratory techniques in biochemistry and molecular biology that require in vitro DNA synthesis usually use DNA primers, since they are more temperature stable. Primers can be designed in laboratory for specific reactions such as polymerase chain reaction (PCR). When designing PCR primers, there are specific measures that must be taken into consideration, like the melting temperature of the primers and the annealing temperature of the reaction itself. Moreover, the DNA binding sequence of the primer in vitro has to be specifically chosen, which is done using a method called basic local alignment search tool (BLAST) that scans the DNA and finds specific and unique regions for the primer to bind.

<span class="mw-page-title-main">RNA polymerase</span> Enzyme that synthesizes RNA from DNA

In molecular biology, RNA polymerase, or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that catalyzes the chemical reactions that synthesize RNA from a DNA template.

<span class="mw-page-title-main">DNA polymerase</span> Form of DNA replication

A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create two identical DNA duplexes from a single original DNA duplex. During this process, DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones. These enzymes catalyze the chemical reaction

DNA primase is an enzyme involved in the replication of DNA and is a type of RNA polymerase. Primase catalyzes the synthesis of a short RNA segment called a primer complementary to a ssDNA template. After this elongation, the RNA piece is removed by a 5' to 3' exonuclease and refilled with DNA.

<span class="mw-page-title-main">DNA polymerase I</span> Family of enzymes

DNA polymerase I is an enzyme that participates in the process of prokaryotic DNA replication. Discovered by Arthur Kornberg in 1956, it was the first known DNA polymerase. It was initially characterized in E. coli and is ubiquitous in prokaryotes. In E. coli and many other bacteria, the gene that encodes Pol I is known as polA. The E. coli Pol I enzyme is composed of 928 amino acids, and is an example of a processive enzyme — it can sequentially catalyze multiple polymerisation steps without releasing the single-stranded template. The physiological function of Pol I is mainly to support repair of damaged DNA, but it also contributes to connecting Okazaki fragments by deleting RNA primers and replacing the ribonucleotides with DNA.

<span class="mw-page-title-main">DNA polymerase III holoenzyme</span> Primary enzyme complex involved in prokaryotic DNA replication

DNA polymerase III holoenzyme is the primary enzyme complex involved in prokaryotic DNA replication. It was discovered by Thomas Kornberg and Malcolm Gefter in 1970. The complex has high processivity and, specifically referring to the replication of the E.coli genome, works in conjunction with four other DNA polymerases. Being the primary holoenzyme involved in replication activity, the DNA Pol III holoenzyme also has proofreading capabilities that corrects replication mistakes by means of exonuclease activity reading 3'→5' and synthesizing 5'→3'. DNA Pol III is a component of the replisome, which is located at the replication fork.

<span class="mw-page-title-main">Okazaki fragments</span> Parts of lagging strand in DNA replication

Okazaki fragments are short sequences of DNA nucleotides which are synthesized discontinuously and later linked together by the enzyme DNA ligase to create the lagging strand during DNA replication. They were discovered in the 1960s by the Japanese molecular biologists Reiji and Tsuneko Okazaki, along with the help of some of their colleagues.

<span class="mw-page-title-main">DNA polymerase II</span> Class of enzymes

DNA polymerase II is a prokaryotic DNA-dependent DNA polymerase encoded by the PolB gene.

<span class="mw-page-title-main">Replisome</span> Molecular complex

The replisome is a complex molecular machine that carries out replication of DNA. The replisome first unwinds double stranded DNA into two single strands. For each of the resulting single strands, a new complementary sequence of DNA is synthesized. The total result is formation of two new double stranded DNA sequences that are exact copies of the original double stranded DNA sequence.

<span class="mw-page-title-main">RNA-dependent RNA polymerase</span> Enzyme that synthesizes RNA from an RNA template

RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. This is in contrast to typical DNA-dependent RNA polymerases, which all organisms use to catalyze the transcription of RNA from a DNA template.

A ribonucleotide tri-phosphate (rNTP) is composed of a ribose sugar, 3 phosphate groups attached via diester bonds to the 5' oxygen on the ribose and a nitrogenous base attached to the 1' carbon on the ribose. rNTP's are also referred to as NTPs while the deoxyribose version is referred to as dNTPs. The nitrogenous base can either be a purine such as a Adenine or Guanine or a pyrimidine such as a Uracil or Cytosine. rNTPs have significant biological uses, they can serve as building blocks of RNA synthesis, primers in DNA replication, stores of chemical energy, chiefly Adenosine triphosphate (ATP) and more.

<span class="mw-page-title-main">Prokaryotic DNA replication</span> DNA Replication in prokaryotes

Prokaryotic DNA Replication is the process by which a prokaryote duplicates its DNA into another copy that is passed on to daughter cells. Although it is often studied in the model organism E. coli, other bacteria show many similarities. Replication is bi-directional and originates at a single origin of replication (OriC). It consists of three steps: Initiation, elongation, and termination.

<span class="mw-page-title-main">Bacterial transcription</span>

Bacterial transcription is the process in which a segment of bacterial DNA is copied into a newly synthesized strand of messenger RNA (mRNA) with use of the enzyme RNA polymerase.

<span class="mw-page-title-main">T7 DNA polymerase</span> Enzyme

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EF-Ts is one of the prokaryotic elongation factors. It is found in human mitochondria as TSFM. It is similar to eukaryotic EF-1B.

<span class="mw-page-title-main">Circular chromosome</span> Type of chromosome

A circular chromosome is a chromosome in bacteria, archaea, mitochondria, and chloroplasts, in the form of a molecule of circular DNA, unlike the linear chromosome of most eukaryotes.

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Nsp12 is a non-structural protein in the Coronavirus genome. Its gene is part of the ORF1ab reading frame and it is part of the pp1ab polyprotein; it is cleaved by 3CLpro.

References

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  12. ↑ Biswas T, Resto-Roldan E, Sawyer SK, Artsimovitch I, Tsodikov OV (December 2012). "A novel non-radioactive primase-pyrophosphatase activity assay and its application to the discovery of inhibitors of Mycobacterium tuberculosis primase DnaG". Nucleic Acids Research. 41 (4): e56. doi:10.1093/nar/gks1292. PMC   3575809 . PMID   23267008.

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