Summary: DNA polymerase III beta subunit, C-terminal domain
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DNA clamp Edit Wikipedia article
A DNA clamp, also known as a sliding clamp, is a protein fold that serves as a processivity-promoting factor in DNA replication. As a critical component of the DNA polymerase III holoenzyme, the clamp protein binds DNA polymerase and prevents this enzyme from dissociating from the template DNA strand. The clamp-polymerase protein–protein interactions are stronger and more specific than the direct interactions between the polymerase and the template DNA strand; because one of the rate-limiting steps in the DNA synthesis reaction is the association of the polymerase with the DNA template, the presence of the sliding clamp dramatically increases the number of nucleotides that the polymerase can add to the growing strand per association event. The presence of the DNA clamp can increase the rate of DNA synthesis up to 1,000-fold compared with a nonprocessive polymerase.
The DNA clamp fold is an α+β protein that assembles into a multimeric structure that completely encircles the DNA double helix as the polymerase adds nucleotides to the growing strand. The DNA clamp assembles on the DNA at the replication fork and "slides" along the DNA with the advancing polymerase, aided by a layer of water molecules in the central pore of the clamp between the DNA and the protein surface. Because of the toroidal shape of the assembled multimer, the clamp cannot dissociate from the template strand without also dissociating into monomers.
The DNA clamp fold is found in bacteria, archaea, eukaryotes and some viruses. In bacteria, the sliding clamp is a homodimer composed of two identical beta subunits of DNA polymerase III and hence is referred to as the beta clamp. In archaea and eukaryotes, it is a trimer composed of three molecules of PCNA. The T4 bacteriophage also uses a sliding clamp, called gp45 that is a trimer similar in structure to PCNA but lacks sequence homology to either PCNA or the bacterial beta clamp.
|Kingdom||Sliding clamp protein||Multimer state||Associated polymerase|
|Bacteria||beta subunit of pol III||dimer||DNA polymerase III|
|Archaea||archaeal PCNA||trimer||pol ε|
|Eukaryote||PCNA||trimer||DNA polymerase delta|
|Virus||gp43 / gp45||trimer||RB69 Pol / T4 Pol|
|DNA polymerase III subunit beta|
|Chromosome||MG1655: 3.88 - 3.88 Mb|
The beta clamp is a specific DNA clamp and a subunit of the DNA polymerase III holoenzyme found in bacteria. Two beta subunits are assembled around the DNA by the gamma subunit and ATP hydrolysis; this assembly is called the pre-initiation complex. After assembly around the DNA, the beta subunits' affinity for the gamma subunit is replaced by an affinity for the alpha and epsilon subunits, which together create the complete holoenzyme. DNA polymerase III is the primary enzyme complex involved in prokaryotic DNA replication.
The gamma complex of DNA polymerase III, composed of γδδ'χψ subunits, catalyzes ATP to chaperone two beta subunits to bind to DNA. Once bound to DNA, the beta subunits can freely slide along double stranded DNA. The beta subunits in turn bind the αε polymerase complex. The α subunit possesses DNA polymerase activity and the ε subunit is a 3’-5’ exonuclease.
The beta chain of bacterial DNA polymerase III is composed of three topologically equivalent domains (N-terminal, central, and C-terminal). Two beta chain molecules are tightly associated to form a closed ring encircling duplex DNA.
As a drug target
|proliferating cell nuclear antigen|
|Locus||Chr. 20 pter-p12|
The sliding clamp in eukaryotes is assembled from a specific subunit of DNA polymerase delta called the proliferating cell nuclear antigen (PCNA). The N-terminal and C-terminal domains of PCNA are topologically identical. Three PCNA molecules are tightly associated to form a closed ring encircling duplex DNA.
The sequence of PCNA is well conserved between plants and animals, indicating a strong selective pressure for structure conservation, and suggesting that this type of DNA replication mechanism is conserved throughout eukaryotes. Homologues of PCNA have also been identified in the archaea (Euryarchaeota and Crenarchaeota) and in Paramecium bursaria Chlorella virus 1 (PBCV-1) and in nuclear polyhedrosis viruses.
|DNA polymerase accessory protein 45|
|Chromosome||1: 0.03 - 0.03 Mb|
The viral gp45 sliding clamp subunit protein contains two domains. Each domain consists of two alpha helices and two beta sheets – the fold is duplicated and has internal pseudo two-fold symmetry. Three gp45 molecules are tightly associated to form a closed ring encircling duplex DNA.
Sliding clamps are loaded onto their associated DNA template strands by specialized proteins known as "sliding clamp loaders", which also disassemble the clamps after replication has completed. The binding sites for these initiator proteins overlap with the binding sites for the DNA polymerase, so the clamp cannot simultaneously associate with a clamp loader and with a polymerase. Thus the clamp will not be actively disassembled while the polymerase remains bound. DNA clamps also associate with other factors involved in DNA and genome homeostasis, such as nucleosome assembly factors, Okazaki fragment ligases, and DNA repair proteins. All of these proteins also share a binding site on the DNA clamp that overlaps with the clamp loader site, ensuring that the clamp will not be removed while any enzyme is still working on the DNA. The activity of the clamp loader requires ATP hydrolysis to "close" the clamp around the DNA.
- "Structural and biochemical studies of human proliferating cell nuclear antigen complexes provide a rationale for cyclin association and inhibitor design". Proc. Natl. Acad. Sci. U.S.A. 102 (6): 1871–6. PMC . PMID 15681588. doi:10.1073/pnas.0406540102.; Kontopidis G, Wu SY, Zheleva DI, Taylor P, McInnes C, Lane DP, Fischer PM, Walkinshaw MD (February 2005).
- V. Mizrahi; R. N. Henrie; J. F. Marlier; K. A. Johnson; S. J. Benkovic (1985). "Rate-limiting steps in the DNA polymerase I reaction pathway". Biochemistry. 24 (15): 4010–4018. doi:10.1021/bi00336a031.
- Bruck I, O'Donnell M (2001). "The ring-type polymerase sliding clamp family". Genome Biol. 2 (1): REVIEWS3001. PMC . PMID 11178284. doi:10.1186/gb-2001-2-1-reviews3001.
- Matsumiya S, Ishino Y, Morikawa K (January 2001). "Crystal structure of an archaeal DNA sliding clamp: Proliferating cell nuclear antigen from Pyrococcus furiosus". Protein Sci. 10 (1): 17–23. PMC . PMID 11266590. doi:10.1110/ps.36401.
- PMID 12832762. doi:10.1107/S0907444903009958.; Oakley AJ, Prosselkov P, Wijffels G, Beck JL, Wilce MC, Dixon NE (July 2003). "Flexibility revealed by the 1.85 Å crystal structure of the beta sliding-clamp subunit of Escherichia coli DNA polymerase III". Acta Crystallogr. D. 59 (Pt 7): 1192–9.
- Lewin, Benjamin (1997). Genes VI. Oxford [Oxfordshire]: Oxford University Press. pp. 484–7. ISBN 0-19-857779-6.
- Lehninger, Albert L (1975). Biochemistry: The Molecular Basis of Cell Structure and Function. New York: Worth Publishers. p. 894. ISBN 0-87901-047-9.
- Stukenberg PT, Studwell-Vaughan PS, O'Donnell M (June 1991). "Mechanism of the sliding beta-clamp of DNA polymerase III holoenzyme". J. Biol. Chem. 266 (17): 11328–34. PMID 2040637.
- Yin Z, Wang Y, Whittell LR, Jergic S, Liu M, Harry E, Dixon NE, Kelso MJ, Beck JL, Oakley AJ (2014). "DNA Replication Is the Target for the Antibacterial Effects of Nonsteroidal Anti-Inflammatory Drugs". Chemistry & Biology. 21: 481–487. PMID 24631121. doi:10.1016/j.chembiol.2014.02.009.
- PMID 8861913. doi:10.1016/S0092-8674(00)81347-1.; Gulbis JM, Kelman Z, Hurwitz J, O'Donnell M, Kuriyan J (October 1996). "Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA". Cell. 87 (2): 297–306.
- Suzuka I, Hata S, Matsuoka M, Kosugi S, Hashimoto J (January 1991). "Highly conserved structure of proliferating cell nuclear antigen (DNA polymerase delta auxiliary protein) gene in plants". Eur. J. Biochem. 195 (2): 571–5. PMID 1671766. doi:10.1111/j.1432-1033.1991.tb15739.x.
- PMID 10698628. doi:10.1006/jmbi.1999.3511.; Moarefi I, Jeruzalmi D, Turner J, O'Donnell M, Kuriyan J (March 2000). "Crystal structure of the DNA polymerase processivity factor of T4 bacteriophage". J. Mol. Biol. 296 (5): 1215–23.
- Steitz TA, Shamoo Y (1999). "Building a replisome from interacting pieces: sliding clamp complexed to a peptide from DNA polymerase and a polymerase editing complex". Cell. 99 (2): 155–166. PMID 10535734. doi:10.1016/S0092-8674(00)81647-5.
- Clamping down on pathogenic bacteria – how to shut down a key DNA polymerase complex. Quips at PDBe
- Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R (2004). Molecular Biology of the Gene. San Francisco: Pearson/Benjamin Cummings. ISBN 0-8053-4635-X.
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DNA polymerase III beta subunit, C-terminal domain Provide feedback
A dimer of the beta subunit of DNA polymerase beta forms a ring which encircles duplex DNA. Each monomer contains three domains of identical topology and DNA clamp fold.
Kong XP, Onrust R, O'Donnell M, Kuriyan J; , Cell 1992;69:425-437.: Three-dimensional structure of the beta subunit of E. coli DNA polymerase III holoenzyme: a sliding DNA clamp. PUBMED:1349852 EPMC:1349852
Internal database links
|Similarity to PfamA using HHSearch:||DNA_pol3_beta|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR022635This entry describes the C-terminal domain of the beta chain of DNA polymerase III. This is a complex, multichain enzyme responsible for most of the replicative synthesis in bacteria. The beta chain is required for initiation of replication from an RNA primer, nucleotide triphosphate (dNTP) residues being added to the 5'-end of the growing DNA chain.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||DNA polymerase III complex (GO:0009360)|
|Molecular function||3'-5' exonuclease activity (GO:0008408)|
|DNA-directed DNA polymerase activity (GO:0003887)|
|DNA binding (GO:0003677)|
|Biological process||DNA replication (GO:0006260)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Sliding DNA clamps are ring-shaped proteins that allow DNA polymerase to achieve high processivity during chromosome replication by tethering the polymerase catalytic subunit to DNA. All of the structures share a 12-fold symmetry around the ring consisting of a simple structural repeat, though there is structural divergence in some of the repeats. Bacterial beta-clamps contain six repeats per subunit with two subunits per ring while the eukaryotic and bacteriophage clamps contain four repeats per subunit with three subunits per ring. Pairs of these repeats form a domain, which has been termed the 'processivity fold'; thus the ring of the sliding clamp contains six domains and therefore is often described as having 6-fold symmetry. A structural representative of a fourth family of processivity fold proteins, namely the herpes simplex virus UL42 protein, is also available. UL42 does not form a ring-shaped clamp, however, but rather functions as a monomer and interacts with DNA quite differently than do sliding clamps; it has been suggested that UL42 resembles a primitive ancestor of sliding clamps .
The clan contains the following 13 members:DNA_pol3_beta DNA_pol3_beta_2 DNA_pol3_beta_3 DNA_PPF gp45-slide_C Herpes_DNAp_acc Herpes_PAP Herpes_UL42 Hus1 PCNA_C PCNA_N Rad1 Rad9
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Seed source:||Pfam-B_631 (release 2.1)|
|Author:||Bateman A, Griffiths-Jones SR|
|Number in seed:||12|
|Number in full:||4534|
|Average length of the domain:||121.50 aa|
|Average identity of full alignment:||25 %|
|Average coverage of the sequence by the domain:||32.86 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
|Download:||download the raw HMM for this family|
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 7 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the DNA_pol3_beta_3 domain has been found. There are 121 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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