Kinetic Theory of ATP-driven Translocases on One-dimensional Polymer Lattices

Young, Mark C.; Kuhl, Sigrid B.; Hippel, Peter H. von

doi:10.1006/jmbi.1994.1099

Cited by 63 publications

(116 citation statements)

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“…A small but reproducible (n ϭ 3) decrease in the k cat⅐DNA was observed in the presence of both mismatched and homoduplex DNA. This decrease in k cat⅐DNA with increasing DNA length is opposite to that found with E. coli helicase II (40) and predicted by a theoretical analysis of ATPdependent translocases (39). Moreover, we observe a 3-4-fold decrease in the K1 ⁄2 ⅐molecules (in units of DNA molecules) and/or an equivalent increase in the K1 ⁄2 ⅐base pairs (in units of DNA base pairs) as the length of the mismatched DNA is increased from 41 to 501 bp.…”

Section: Resultscontrasting

confidence: 97%

“…The method is similar to that described by Young et al (39) for ATP hydrolysis-driven translocases. A description of the kinetic steps and net rate constants associated with hMSH2-hMSH6 mismatch recognition (k 1 Ј), adenosine nucleotide exchange (k 2 Ј), hydrolysis-independent diffusion (k t ), and ATP hydrolysis at the terminal boundary of the DNA (k atp ; k d ) are shown in Scheme I.…”

Section: Discussionmentioning

confidence: 99%

“…However, ADP may remain associated with the protein complex, and its dissociation (during ADP3 ATP exchange) may be embedded in the k 2 Ј net rate constant of Scheme I (or k 1 Ј net rate as outlined in Scheme III). The average apparent rate constant for travel to the end of a lattice (in this case DNA) has been defined as k t (39) and was derived from a kinetic formalism similar to Scheme II (note that k 1 and k Ϫ1 are not related to those found in Scheme I or Scheme III and merely formalize the stepwise movement of the E*ATP complex along the DNA length from position 0 3 1 3 2 3 . .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, Equations 1 and 2 adapted from Young et al (39) for unidirectional and random walk translocation appear analogous for a hydrolysis-independent sliding clamp (Scheme III). We next consider a further simplification of the kinetic model that employs the form expressed by Young et al (39), which includes DNA (mismatch) binding and ADP3, which ATP exchange in a single net rate constant k 1 Ј (that now includes k 1 Ј and k 2 Ј from Scheme I) as illustrated in Scheme III.…”

Section: Discussionmentioning

confidence: 99%

“…We next consider a further simplification of the kinetic model that employs the form expressed by Young et al (39), which includes DNA (mismatch) binding and ADP3, which ATP exchange in a single net rate constant k 1 Ј (that now includes k 1 Ј and k 2 Ј from Scheme I) as illustrated in Scheme III. In this scheme, we imagine that ADP does not dissociate from the protein until ADP3 ATP exchange (termed EЈ); the kinetic rate constant for ATP hydrolysis (k atp ) need only require dissociation of P I , which is the measure of ATPase described in the text.…”

Section: Discussionmentioning

confidence: 99%

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The Role of Mismatched Nucleotides in Activating the hMSH2-hMSH6 Molecular Switch

Gradia

Acharya

Fishel

2000

Journal of Biological Chemistry

103

118

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We have previously shown that hMSH2-hMSH6 contains an intrinsic ATPase which is activated by mismatch-provoked ADP3 ATP exchange that coordinately induces the formation of a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone (1, 2). These studies suggested that mismatch repair could be propagated by a signaling event transduced via diffusion of ATP-bound hMSH2-hMSH6 molecular switches to the DNA repair machinery Mismatch repair (MMR)1 is an important cellular pathway that facilitates genome stability by correcting mismatched nucleotides in DNA that arise from chemical and physical damage, replication errors, and recombination events between heteroallelic parental DNAs (for review see Ref. 6). Mutation of several of the human MMR genes have been shown to result in a mutator phenotype and are associated with a common cancer predisposition syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), as well as a variety of sporadic tumors (7,8).Initiation of MMR is fundamentally dependent on the prototypical Escherichia coli MutS or its eucaryotic homologs: a highly conserved family of proteins responsible for mispair recognition (for review see Ref. 9). The bacterial MutS protein appears to recognize mispaired DNA as a homodimer, while the eucaryotic MSHs (MutS homologs) appear to function as heterodimers of . Like their yeast counterpart, the human hMSH2-hMSH6 heterodimer primarily recognizes and participates in the repair of single-base and small insertion/deletion DNA mismatches, while the hMSH2-hMSH3 heterodimer is associated with the repair of small and large insertion/deletion DNA mismatches (12)(13)(14). Homology between the MutS homologs is largely based upon a highly conserved Walker-A/B adenosine nucleotide and magnesium-binding domain (3, 9). Although aspects of ATP binding/hydrolysis by the bacterial and yeast MutS homologs have been examined (15-17), more comprehensive studies of the human hMSH2-hMSH6 heterodimer have demonstrated coupled ATP and DNA binding properties as well as an intrinsic ATPase activity that is stimulated by mispaired DNA (1,2,5,18,19). A defining observation is that binding to mismatched DNA by MutS and hMSH2-hMSH6 is abolished in the presence of ATP (1,10,20). The ATP-induced release of E. coli MutS from mispaired DNA has been reported to occur by hydrolysisdriven translocation of the protein along the DNA backbone (4). This conclusion is based on the appearance of growing loop structures observed by electron microscopy that depend on MutS, MutL, and ATP. Moreover, the poorly hydrolyzable analog of ATP, ATP␥S, appears to block the growth of these loops, which has been interpreted to suggest a requirement for ATP hydrolysis.An alternative model for signaling MMR suggests that hMSH2-hMSH6 functions as an adenosine nucleotide-regulated molecular switch (1-3). This conclusion is grounded on the biochemical properties of the hMSH2-hMSH6 ATPase and the observation that ADP and ATP have opposing effects on mispair binding. These studies have further demo...

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Section: Resultscontrasting

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

The Role of Mismatched Nucleotides in Activating the hMSH2-hMSH6 Molecular Switch

Gradia

Acharya

Fishel

2000

Journal of Biological Chemistry

103

118

View full text Add to dashboard Cite

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Mitochondrial helicase Irc3 translocates along double‐stranded DNA

et al. 2017

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Irc3 is a superfamily II helicase required for mitochondrial DNA stability in Saccharomyces cerevisiae. Irc3 remodels branched DNA structures, including substrates without extensive single-stranded regions. Therefore, it is unlikely that Irc3 uses the conventional single-stranded DNA translocase mechanism utilized by most helicases. Here, we demonstrate that Irc3 disrupts partially triple-stranded DNA structures in an ATP-dependent manner. Our kinetic experiments indicate that the rate of ATP hydrolysis by Irc3 is dependent on the length of the double-stranded DNA cosubstrate. Furthermore, the previously uncharacterized C-terminal region of Irc3 is essential for these two characteristic features and forms a high affinity complex with branched DNA. Together, our experiments demonstrate that Irc3 has double-stranded DNA translocase activity.

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Type III restriction endonucleases translocate DNA in a reaction driven by recognition site-specific ATP hydrolysis.

et al. 1995

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Type III restriction/modification systems recognize short non‐palindromic sequences, only one strand of which can be methylated. Replication of type III‐modified DNA produces completely unmethylated recognition sites which, according to classical mechanisms of restriction, should be signals for restriction. We have shown previously that suicidal restriction by the type III enzyme EcoP15I is prevented if all the unmodified sites are in the same orientation: restriction by EcoP15I requires a pair of unmethylated, inversely oriented recognition sites. We have now addressed the molecular mechanism of site orientation‐specific DNA restriction. EcoP15I is demonstrated to possess an intrinsic ATPase activity, the potential driving force of DNA translocation. The ATPase activity is uniquely recognition site‐specific, but EcoP15I‐modified sites also support the reaction. EcoP15I DNA restriction patterns are shown to be predetermined by the enzyme‐to‐site ratio, in that site‐saturating enzyme levels elicit cleavage exclusively between the closest pair of head‐to‐head oriented sites. DNA restriction is blocked by Lac repressor bound in the intervening sequence between the two EcoP15I sites. These results rule out DNA looping and strongly suggest that cleavage is triggered by the close proximity of two convergently tracking EcoP15I‐DNA complexes.

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Kinetic Theory of ATP-driven Translocases on One-dimensional Polymer Lattices

Cited by 63 publications

References 0 publications

The Role of Mismatched Nucleotides in Activating the hMSH2-hMSH6 Molecular Switch

The Role of Mismatched Nucleotides in Activating the hMSH2-hMSH6 Molecular Switch

Mitochondrial helicase Irc3 translocates along double‐stranded DNA

Type III restriction endonucleases translocate DNA in a reaction driven by recognition site-specific ATP hydrolysis.

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