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==Bacterial RNA Polymerase: New Insights on a Fundamental Molecular Machine==
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=Alpha Subunit of ''Thermus aquaticus'' DNA Polymerase III=
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RNA polymerase (RNAP) is an information-processing molecular machine that copies DNA into RNA. It is a multi-subunit complex found in every living organism. Bacterial RNAP contains six subunits (ββ’α2ωσ). This model focuses on the β’ subunit of RNAP elongation complex (EC) of ''Thermus thermophilus'' that contains the active site sequence and several structures involved in the catalytic mechanism. The active site channel accommodates double stranded DNA and an RNA-DNA hybrid helix. The secondary channel allows nucleotides (NTPs) to enter the active site, and the exit channel guides the growing RNA transcript out of the complex. The DNA template strand becomes kinked as it moves through the active site channel and is separated from the non-template strand. This kink allows one dNTP at a time to become available for nucleotide addition once it translocates to the +1 site. The bridge helix (BH) and trigger loop (TL) work together as a “swinging gate” to enhance the catalytic action by facilitating NTP addition. In the crystal structure of the EC without NTP in the active site, the TL (β’ 1236-1265) is unstructured. In the EC crystal structure with a non-hydrolysable nucleotide (AMPcPP), the TL folds into two anti-parallel helices (trigger helix, TH) that interact with the adjacent BH to create a three-helical bundle forming a catalytically active complex. The other structures that are functionally important in the β’ subunit are the “lid” (β’ 525-539) that cleaves the RNA-DNA hybrid, directing the newly formed RNA out through the exit channel, and the “rudder” (β’ 582-602) that helps to stabilize the DNA helix and the RNA-DNA hybrid in the active site channel.
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==Introduction==
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===Role of DNA Polymerase in Replication===
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The primary function of DNA polymerase is to replicate the DNA of an organism. [http://en.wikipedia.org/wiki/DNA_replication DNA replication] occurs just prior to cell division and is necessary for growth and reproduction of a living organism (see [[DNA Replication, Transcription and Translation]]). [[DNA]] consists of two strands of hydrogen-bonded deoxyribonucleotides (dNTPs) running anti-parallel to each other in a double helix. The deoxyribonucleotides that make up DNA consist of a nitrogen base, a deoxyribose sugar group, and a phosphate. The DNA backbone is composed of sugar groups and phosphates joined with phosphodiester bonds, giving it a negative charge. The nitrogen bases of the deoxyribonucleotides extend into the helix and form Watson-Crick base pairs (A-T and C-G) stabilized by hydrogen bonds. The result is double-stranded DNA.
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==RNA Polymerase Elongation Complex==
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The replisome is an enzymatic complex with multiple subunits (see [http://origin-ars.els-cdn.com/content/image/1-s2.0-S1570963909001897-gr3.jpg Replisome Diagram]). The core DNA polymerase subunits are α, ε, and θ, which are adjacent to the the β-clamp. This tutorial will focus on the α-subunit which contains the catalytic site for dNTP addition to the primer strand.
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The RNAP holoenzyme is a molecular machine comprised of six subunits that copies DNA to RNA. RNAP initially binds to DNA at the promoter to form the closed complex. The DNA surrounding the promoter sequence unwinds to form the open complex consisting of a 17 base pair transcription bubble (link to Pingry model with footnote for different nomenclature). The transcribed template strand is held inside the active site channel while the non-template strand is held between the rudder and clamp helices, away from the active site. RNAP releases from the promoter and transitions to the elongation complex that moves along the template strand, adding nucleotides to the 3’ hydroxyl of the RNA at a rate of 30 to 100 nucleotides per second. The β’ subunit contains structures and forms channels that are crucial to this process.
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Ribonucleotides enter through the secondary channel (15 x 20 Å)(link to Pingry model). The ribonucleotide is initially positioned at the pre-insertion site with its base forming hydrogen bonds with the template base and the triphosphate facing the active site. Subsequent movement of the ribonucleotide to the insertion site positions the triphosphate close enough to the active site for catalysis to occur.
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===Prokaryotic DNA Polymerases===
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Several differences exist between replication in prokaryotes and eukaryotes. Eukaryotic DNA is complexed with histones that must be removed and replaced during each round of replication<ref name='eukaryote'>Winning, R.S. (2001). "DNA Replication." Eastern Michigan University. Retrieved from http://www.emunix.emich.edu/~rwinning/genetics/replic4.htm. </ref>. Organelles within the eukaryotic cell, such as mitochondria, may contain DNA that also must be replicated <ref name='eukaryote' />. Prokaryotic chromosomes are circular, whereas eukaryotic chromosomes are linear<ref name='eukaryote' />. The increased complexity of eukaryotic DNA replication has resulted in at least five DNA polymerases being discovered thus far<ref name='eukaryote' />.
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The active and secondary channels are separated by the bridge helix (link to Pingry model). Besides forming channels, the bridge helix interacts with a structure called the trigger loop, which is unstructured in this model. When a nucleotide is present, the bridge helix induces a conformation change in the trigger loop so it becomes the trigger helix. The trigger helix acts as a swinging gate while guiding ribonucleotides into their correct orientation to meet the 3’ hydroxyl of the growing RNA transcript. The trigger helix also reduces the size of the secondary channel to 11 x 11 Å, which prevents diffusion of the complementary nucleotide away from the active site while simultaneously preventing interference from other nucleotides.
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Prokaryotes, on the other hand, utilize three DNA polymerases. DNA polymerases I and II are primarily involved in DNA repair, specifically in using their 3'-5' exonuclease activity to remove faulty base pairs <ref name='eukaryote' />. [http://en.wikipedia.org/wiki/DNA_polymerase_III DNA polymerase III] is the main replicative polymerase in bacteria. The DNA polymerase III α-subunit shown below is that of ''Thermus aquaticus'', commonly referred to as Taq. This crystallized structure of the α-subunit of Taq DNA polymerase III contains DNA, DNA polymerase III, and an incoming dNTP (referred to as the ternary complex)<ref name='wing'>PMID: 18691598</ref>. Taq DNA polymerase III, a replicative polymerase, is homologous to that of ''Escherichia coli'' and also Polβ, a eukaryotic polymerase specializing in repair instead of replication <ref name='wing' />.
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===β’ Subunit of ''Thermus thermophilus'' RNAP===
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===Learning Objectives===
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This is the beta-prime subunit of the elongation complex of Thermus thermophilus RNAP. The beta-prime subunit contains structures and channels required for RNA transcription.
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* How does the α subunit of DNA polymerase III contact DNA?
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* Which domains select for deoxyribonucleotides?
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* Which domains form the catalytic site?
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* Which domains form the DNA exit channel?
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DNA in the active site channel provides the genetic information for RNA transcription. The active site channel that accommodates the downstream DNA (dwDNA) and RNA/DNA hybrid is 27 Å wide. The template strand provides the complementary sequence for the RNA transcript and continues along the active site channel adjacent to the active site. The non-template strand, or coding strand, is held away from the active site by the rudder and clamp helices (not shown in the model).
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===Challenge Questions===
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COMING SOON
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The template strand is kinked at the junction between the dwDNA and the RNA/DNA hybrid. The base pair at the +2 site is distorted. The unpaired acceptor DNA at position +1 on the template strand occurs at the kink.
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==Components of ''Taq'' DNA Polymerase III α-Subunit==
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===Videos Detailing Functional Core and Active Site===
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<swf width="500" height="330">http://cbm.msoe.edu/markMyweb/crestVideos/CrestUWMilwaukee2012-Video1.swf</swf>
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<swf width="500" height="330">http://cbm.msoe.edu/markMyweb/crestVideos/CrestUWMilwaukee2012-Video2.swf</swf>
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Upstream of the active site is the RNA/DNA hybrid. This hybrid structure is comprised of the template strand and the complementary RNA transcript hydrogen-bonded to the template bases. The most recently formed hybrid bond is located at the -1 site.
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<StructureSection load='3e0d' size='400' side='right' caption='DNA Polymerase III Alpha Subunit (PDB entry [[3e0d]])' scene='46/461391/Dnapol_overview/5'>
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===Important Domains===
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The fingers, palm and thumb domains of DNA polymerase III are highly conserved <ref name='kohlstaedt'>PMID: 1377403</ref>. They are nicknamed as such because the structures resemble a closed hand gripping double-stranded DNA. Typically the fingers interact with the incoming deoxyribonucleotide, the palm positions catalytic ions, and the thumb holds the DNA template <ref name='steitz'>PMID: 10364165</ref>.These domains form binding pockets for both DNA and incoming dNTPs<ref name='wing' />. They are also involved in correct dNTP selection, position and addition along with DNA interactions <ref name='wing' />.
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The rudder stabilizes the dwDNA and the upstream RNA/DNA hybrid with numerous sidechain interactions. The side chains of two arginine residues are shown contacting the dwDNA and RNA/DNA structures.
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* <scene name='46/461391/Dnapol_palm/4'>Palm</scene> (residues 286-492 and 575-622, in light green) - The palm domain contains the catalytic site for nucleotide addition, including three highly conserved aspartates <scene name='46/461391/Dnapol_aspartates/3'>(Taq463, Taq465 and Taq618)</scene><ref name='wing' />. The palm domain also aids in positioning the 3' primer hydroxyl group and incoming deoxyribonucleotides so that the conjugate base is in the correct orientation for catalysis (i.e., the incoming dNTP base near the primer base and triphosphate adjacent to the catalytic aspartates)<ref name='wing' />.
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* <scene name='46/461391/Dnapol_fingers/3'>Fingers</scene> (residues 623-835, in light blue) - The fingers domain selects for deoxyribonucleotides over ribonucleotides by evaluating the sugar group<ref name='bailey'>PMID: 16959569</ref>. It also aids in positioning the incoming deoxyribonucleotides so that the conjugate base is in the correct orientation for catalysis<ref name='wing' />. The fingers domain forms part of the active site<ref name='wing' />.
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* <scene name='46/461391/Dnapol_thumb/3'>Thumb</scene> (residues 493-574, in salmon) - The thumb domain forms part of the DNA exit channel and contains many residues that interact with the DNA<ref name='wing' />.
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* <scene name='46/461391/Dnapol_betabinding/3'>β-Binding Domain</scene> (residues 836-1012, in light purple) - The β-binding domain binds the β-sliding clamp and also positions double-stranded DNA<ref name='wing' />.
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* <scene name='46/461391/Dnapol_ctd/4'>C-Terminal Domain (CTD)</scene> (residues 1013-1220, in gray) - The CTD contains an oligonucleotide binding-fold (OB-fold) that buries single-stranded DNA in a surface groove<ref name='wing' />.
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* <scene name='46/461391/Dnapol_php/3'>Polymerase and Histidinol Phosphatase (PHP) Domain</scene> (residues 1-285, in gray) - The PHP domain forms part of the DNA exit channel<ref name='wing' />. It may have proofreading function via Zn<sup>2+</sup>-dependent exonuclease activity, although this is yet to be determined<ref name='stano'>PMID: 16604084</ref>.
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* <scene name='46/461391/Dnapol_dntp/3'>Incoming Deoxyribonucleotide (dNTP)</scene> - This is the incoming deoxyribonucleotide that must undergo sugar selection, orientation and positioning, stabilization, catalysis, and addition to the nascent DNA chain<ref name='wing' />.
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* <scene name='46/461391/Dnapol_aspartates/3'>Catalytic Aspartates</scene> (residues 463, 465 and 618) - These aspartate residues are highly conserved and essential to catalysis <ref name='wing' /><ref name='pritchard'>PMID: 9887268 </ref>.
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</StructureSection>
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The internal chamber can accommodate the 9 bp RNA/DNA hybrid. At the upstream position the hybrid meets the lid that sterically blocks continued elongation of the hybrid. The lid facilitates cleavage of the H-bond releasing the growing RNA transcript into the exit channel. As the bond is cleaved, the template strand moves one position forward through the active site channel. This process is called translocation. This allows the only unpaired template nucleotide to move into the +1 site adjacent to the active site where nucleotide addition occurs.
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===DNA Interactions & Conformational Changes===
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The thumb domain uses multiple positively-charged residues within two α-helices to interact with the DNA substrate at the minor groove (Taq500-511 and Taq515-526)<ref name='wing' />. The β-binding domain interacts with DNA via its helix-hairpin-helix (HhH) motif (Taq892-910) and adjacent loops (Taq846-852 and Taq923-927)<ref name='wing' />. The HhH motif directly contacts the sugar-phosphate backbone of DNA at the minor groove<ref name='wing' />. Contact is made using positively-charged residues <scene name='46/461391/Dnapol_backboneresidues/2'>(Taq895, Taq932 and Taq933)</scene> on the negatively-charged backbone<ref name='wing' />. The PHP domain may contact the DNA at a loop <scene name='46/461391/Dnapol_phpdna/4'>(Taq 232-241)</scene><ref name='wing' />.
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The active site consists of three highly conserved aspartate sidechains chelated to the Mg2+ ion required for catalysis. Phosphodiester bond formation that occurs during catalysis involves the active site Mg2+ ion, the bridge helix, and the trigger helix, which is unstructured in this model due to its high mobility. During nucleotide addition, the alpha-phosphate of the incoming ribonucleotide triphosphate (NTP) reacts with the 3’ hydroxyl of the last ribonucleotide in the RNA transcript.
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Before contact is made, the thumb and PHP domains block the positioning of double-stranded DNA<ref name='wing' />. Upon contact, the PHP domain rotates away from the DNA, allowing the thumb to contact the minor groove of the DNA<ref name='wing' />. The β-binding domain, fingers and thumb also adjust<ref name='wing' />.
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After catalysis the RNA/DNA hybrid moves in the -1 site, and the ribonucleotide in this bond provides the 3’ hydroxyl for the next incoming NTP.
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==Nucleotide Addition==
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<StructureSection load='3e0d' size='400' side='left' caption='DNA polymerase III α-subunit (PDB entry [[3e0d]])' scene='46/461391/Dnapol_overview/5'>
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===Video of Nucleotide Addition===
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<swf width="564" height="330">http://cbm.msoe.edu/markMyweb/crestVideos/CrestUWMilwaukee2012-Video3.swf</swf>
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===Nucleotide Addition and the Trigger Loop===
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===Deoxyribonucleotide Selection and Positioning===
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This section will feature a video explaining the conformational changes undergone by the trigger loop/helix when switching from the pre-insertion complex to the insertion complex.
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* Nucleotides enter the complex through a <scene name='46/461391/Dnapol_dntpentry/3'>groove formed by the PHP, fingers and palm domains</scene><ref name='wing' />.
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* <scene name='46/461391/Dnapol_his817tyr821/4'>Histidine 817 and Tyrosine 821</scene> evaluate sugar groups on incoming nucleotides and select for dNTPs<ref name='bailey' />.
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* If a ribonucleotide or an incorrectly matched dNTP enters the nucleotide binding pocket, misalignment occurs and catalysis cannot happen.
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* Highly conserved arginine residues <scene name='46/461391/Dnapol_positioning/3'>(Taq452, Taq458, Taq766 and Taq767)</scene> interact with the triphosphate of the incoming dNTP <ref name='bailey' /><ref name='wing' />. These arginine residues facilitate base pairing between the primer base and dNTP through orientation of the nucleotide<ref name='bailey' /><ref name='wing' />.
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* The incoming dNTP is also coordinated by <scene name='46/461391/Dnapol_gs767/3'> the GS motif </scene>(Taq G425-S426) via interactions with the γ-phosphate of the dNTP<ref name='wing' />. The GS motif is absolutely conserved<ref name='aravind'>PMID: 10075991</ref>.
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* The 3' end of the primer strand is positioned by formation of a salt bridge between <scene name='46/461391/Dnapol_lys616/4'>Lysine 616 and the 3' primer terminal phosphate</scene><ref name='wing' />.
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==2011 UW-Milwaukee CREST Team==
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===Catalysis===
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===Team===
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* All polymerases employ a two metal ion mechanism for catalysis<ref name='steitzsmerdon'>PMID: 7528445</ref>.
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Catherine L Dornfeld
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* One metal ion is found near the conserved aspartate residues and incoming dNTP triphosphate, while the <scene name='46/461391/Dnapol_metalion/3'>second metal ion</scene> is coordinated by the 3' primer hydroxyl group and the α-phosphate of the incoming dNTP<ref name='wing' />.
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* The 3' hydroxyl group attacks the α-phosphate of the incoming dNTP. A phosphodiester bond is formed between the 3' hydroxyl of the primer strand and the 5' α-phosphate group of the incoming dNTP. A pyrophosphate consisting of the incoming dNTP's β- and γ-phosphates is released.
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Christopher Hanna
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</StructureSection>
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Jason Slaasted
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==2012 UW-Milwaukee CREST Team==
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===Model Researchers and Designers===
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Joseph Johnston, Bryan Landrie and Anne Marie Wannamaker
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===Acknowledgments===
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===Abstract===
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Steven Forst, Ph.D., University of Wisconsin-Milwaukee
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COMING SOON
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Rick Gourse, Ph.D., University of Wisconsin-Madison
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MSOE Center for BioMolecular Modeling
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NSF CREST program
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==References==
==References==
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<references />
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Snyder, L & Champness, W (2007). ''Molecular genetics of bacteria'' (3rd ed.). Washington, D.C.: ASM Press.
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Vassylyev DG, Vassylyeva MN, Zhang J, Palangat M, Artsimovitch I, Landick R. ''Structural basis for substrate loading in bacterial RNA polymerase''. Nature. 2007 Jul 12;448(7150):163-8. Epub 2007 Jun 20. PMID:17581591 doi:10.1038/nature05931
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Vassylyev DG, Vassylyeva MN, Perederina A, Tahirov TH, Artsimovitch I. ''Structural basis for transcription elongation by bacterial RNA polymerase''. Nature. 2007 Jul 12;448(7150):157-62. Epub 2007 Jun 20. PMID:17581590 doi:10.1038/nature05932
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Current revision

Contents

Alpha Subunit of Thermus aquaticus DNA Polymerase III

Introduction

Role of DNA Polymerase in Replication

The primary function of DNA polymerase is to replicate the DNA of an organism. DNA replication occurs just prior to cell division and is necessary for growth and reproduction of a living organism (see DNA Replication, Transcription and Translation). DNA consists of two strands of hydrogen-bonded deoxyribonucleotides (dNTPs) running anti-parallel to each other in a double helix. The deoxyribonucleotides that make up DNA consist of a nitrogen base, a deoxyribose sugar group, and a phosphate. The DNA backbone is composed of sugar groups and phosphates joined with phosphodiester bonds, giving it a negative charge. The nitrogen bases of the deoxyribonucleotides extend into the helix and form Watson-Crick base pairs (A-T and C-G) stabilized by hydrogen bonds. The result is double-stranded DNA.

The replisome is an enzymatic complex with multiple subunits (see Replisome Diagram). The core DNA polymerase subunits are α, ε, and θ, which are adjacent to the the β-clamp. This tutorial will focus on the α-subunit which contains the catalytic site for dNTP addition to the primer strand.

Prokaryotic DNA Polymerases

Several differences exist between replication in prokaryotes and eukaryotes. Eukaryotic DNA is complexed with histones that must be removed and replaced during each round of replication[1]. Organelles within the eukaryotic cell, such as mitochondria, may contain DNA that also must be replicated [1]. Prokaryotic chromosomes are circular, whereas eukaryotic chromosomes are linear[1]. The increased complexity of eukaryotic DNA replication has resulted in at least five DNA polymerases being discovered thus far[1].

Prokaryotes, on the other hand, utilize three DNA polymerases. DNA polymerases I and II are primarily involved in DNA repair, specifically in using their 3'-5' exonuclease activity to remove faulty base pairs [1]. DNA polymerase III is the main replicative polymerase in bacteria. The DNA polymerase III α-subunit shown below is that of Thermus aquaticus, commonly referred to as Taq. This crystallized structure of the α-subunit of Taq DNA polymerase III contains DNA, DNA polymerase III, and an incoming dNTP (referred to as the ternary complex)[2]. Taq DNA polymerase III, a replicative polymerase, is homologous to that of Escherichia coli and also Polβ, a eukaryotic polymerase specializing in repair instead of replication [2].

Learning Objectives

  • How does the α subunit of DNA polymerase III contact DNA?
  • Which domains select for deoxyribonucleotides?
  • Which domains form the catalytic site?
  • Which domains form the DNA exit channel?

Challenge Questions

COMING SOON

Components of Taq DNA Polymerase III α-Subunit

Videos Detailing Functional Core and Active Site

<swf width="500" height="330">http://cbm.msoe.edu/markMyweb/crestVideos/CrestUWMilwaukee2012-Video1.swf</swf> <swf width="500" height="330">http://cbm.msoe.edu/markMyweb/crestVideos/CrestUWMilwaukee2012-Video2.swf</swf>

DNA Polymerase III Alpha Subunit (PDB entry 3e0d)

Drag the structure with the mouse to rotate

DNA Interactions & Conformational Changes

The thumb domain uses multiple positively-charged residues within two α-helices to interact with the DNA substrate at the minor groove (Taq500-511 and Taq515-526)[2]. The β-binding domain interacts with DNA via its helix-hairpin-helix (HhH) motif (Taq892-910) and adjacent loops (Taq846-852 and Taq923-927)[2]. The HhH motif directly contacts the sugar-phosphate backbone of DNA at the minor groove[2]. Contact is made using positively-charged residues on the negatively-charged backbone[2]. The PHP domain may contact the DNA at a loop [2].

Before contact is made, the thumb and PHP domains block the positioning of double-stranded DNA[2]. Upon contact, the PHP domain rotates away from the DNA, allowing the thumb to contact the minor groove of the DNA[2]. The β-binding domain, fingers and thumb also adjust[2].

Nucleotide Addition

DNA polymerase III α-subunit (PDB entry 3e0d)

Drag the structure with the mouse to rotate

2012 UW-Milwaukee CREST Team

Model Researchers and Designers

Joseph Johnston, Bryan Landrie and Anne Marie Wannamaker

Abstract

COMING SOON

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Winning, R.S. (2001). "DNA Replication." Eastern Michigan University. Retrieved from http://www.emunix.emich.edu/~rwinning/genetics/replic4.htm.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 Wing RA, Bailey S, Steitz TA. Insights into the replisome from the structure of a ternary complex of the DNA polymerase III alpha-subunit. J Mol Biol. 2008 Oct 17;382(4):859-69. Epub 2008 Jul 27. PMID:18691598 doi:10.1016/j.jmb.2008.07.058
  3. ↑ Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 1992 Jun 26;256(5065):1783-90. PMID:1377403 doi:[http://dx.doi.org/10.1126/science.1377403 http://dx.doi.org/10.1126/science.1377403
  4. ↑ Steitz TA. DNA polymerases: structural diversity and common mechanisms. J Biol Chem. 1999 Jun 18;274(25):17395-8. PMID:10364165
  5. ↑ 5.0 5.1 5.2 5.3 Bailey S, Wing RA, Steitz TA. The structure of T. aquaticus DNA polymerase III is distinct from eukaryotic replicative DNA polymerases. Cell. 2006 Sep 8;126(5):893-904. PMID:16959569 doi:10.1016/j.cell.2006.07.027
  6. ↑ Stano NM, Chen J, McHenry CS. A coproofreading Zn(2+)-dependent exonuclease within a bacterial replicase. Nat Struct Mol Biol. 2006 May;13(5):458-9. Epub 2006 Apr 9. PMID:16604084 doi:10.1038/nsmb1078
  7. ↑ Pritchard AE, McHenry CS. Identification of the acidic residues in the active site of DNA polymerase III. J Mol Biol. 1999 Jan 22;285(3):1067-80. PMID:9887268 doi:10.1006/jmbi.1998.2352
  8. ↑ Aravind L, Koonin EV. DNA polymerase beta-like nucleotidyltransferase superfamily: identification of three new families, classification and evolutionary history. Nucleic Acids Res. 1999 Apr 1;27(7):1609-18. PMID:10075991
  9. ↑ Steitz TA, Smerdon SJ, Jager J, Joyce CM. A unified polymerase mechanism for nonhomologous DNA and RNA polymerases. Science. 1994 Dec 23;266(5193):2022-5. PMID:7528445

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