Transformation of MutL by ATP Binding and Hydrolysis

Ban, Changill; Junop, M.S.; Yang, Wei

doi:10.1016/s0092-8674(00)80717-5

Cited by 371 publications

(575 citation statements)

References 38 publications

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“…The lid loses α-helical content and gains flexibility as a consequence of interactions with the nucleotide (Colombo et al, 2008). This is in contrast to other GHKL family members such as MutL where the lid becomes more ordered in the presence of nucleotide (Ban et al, 1999). Two additional lid positions are seen in different crystals of ADP-bound HtpG ( Figure 4D) (Shiau et al, 2006).…”

Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 92%

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

269

254

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The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1-2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organismdependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90's conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90's conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

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Section: Local Structural Changes In the Ntd Due To Nucleotide Bindingmentioning

confidence: 92%

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

269

254

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“…Nonetheless, the data shown in this study indicate that the stimulation reaction requires MutLα ATPase activity and two novel activities identified in this study (Figure 6), i.e., pri-miRNA binding and interactions with Drosha and DGCR8. Because ATP hydrolysis by MutL leads to conformational changes of the protein, which modulate interactions between MutL and other MMR components [40,41], it is possible that ATP hydrolysis by MutLα during the pri-miRNA processing reaction promotes a required conformational change of MutLα and/or its binding partners in the context of this reaction. This possibility is consistent with the observation that MutLαEA, which is defective in normal ATPase activity ( Figure 6B), does not stimulate, but inhibits, miRNA processing ( Figure 6C).…”

Section: Guogen Mao Et Al 981mentioning

confidence: 99%

Modulation of microRNA processing by mismatch repair protein MutLα

et al. 2012

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MicroRNAs (miRNAs) are critical post-transcriptional regulators and are derived from hairpin-shaped primary transcripts via a series of processing steps. However, how the production of individual miRNAs is regulated remains largely unknown. Similarly, loss or overexpression of the key mismatch repair protein MutLα (MLH1-PMS2 heterodimer) leads to genome instability and tumorigenesis, but the mechanisms controlling MutLα expression are unknown. Here we demonstrate in vitro and in vivo that MLH1 and miR-422a participate in a feedback loop that regulates the level of both molecules. Using a defined in-vitro miRNA processing system, we show that MutLα stimulates the conversion of pri-miR-422a to pre-miR-422a, as well as the processing of other miRNAs tested, implicating MutLα as a general stimulating factor for miRNA biogenesis. This newly identified MutLα function requires its ATPase and pri-miRNA binding activities. In contrast, miR-422a downregulates MutLα levels by suppressing MLH1 expression through base pairing with the MLH1 3′-untranslated region. A model depicting this feedback mechanism is discussed.

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“…In 1998, its ATPase activity was identified and shown to modulate the conformation and DNA binding properties of MutL (Fig. 2B) [14,15]. Now with the proper cofactors, MutLα is found to be an endonuclease!…”

mentioning

confidence: 99%

“…Kadyrov et al showed that mutations that abolish MutLα ATP hydrolysis also prevent the 3′ break-directed incision [4]. The ATPase domain in the N-terminal region of MutL is highly conserved and resembles those of DNA gyrase and topoisomerase II [14,15]. Can MutLα sense DNA topology?…”

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confidence: 99%

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Human MutLα: The jack of all trades in MMR is also an endonuclease

Yang

2007

DNA Repair

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SummaryRecently, Paul Modrich's group reported the discovery of an intrinsic endonuclease activity for human MutLα. This breakthrough provides a satisfactory answer to the longstanding puzzle of a missing nuclease activity in human mismatch repair and will undoubtedly lead to new investigations of DNA repair and replication. Here, the implications of this exciting new finding are discussed in the context of mismatch repair in E. coli and humans.Correction of replication errors by mismatch repair (MMR) has long been recognized as critical for genomic stability. Inactivation of MMR in humans has been implicated in > 90% of hereditary nonpolyposis colorectal cancers [1]. Like every DNA repair process, the success of MMR depends on two essential steps: lesion detection and removal. MMR is unique in two aspects. The targets of repair are normal rather than damaged nucleotides, and nucleotide removal has to be specific to the newly synthesized daughter strand and not the template. E. coli MMR is the best understood and has been fully reconstituted in vitro using a dozen or so purified proteins [2,3]. Recognition of a normal nucleotide that fails to make a Watson-Crick base pair in a DNA duplex is accomplished by the MutS protein. The strand specificity of MMR in E. coli is conferred by a sequence and methylation specific endonuclease MutH, which makes an incision (nick) 5′ to a GATC sequence in the unmethylated daughter strand. The GATC sequence may be several hundred base pairs from the mismatch on either the 5′ or 3′ side (Fig. 1A). The direction of daughter strand removal is strongly biased towards the shorter track between the nick and mismatch in a circular genome. The degradation of hundreds to a thousand nucleotides is carried out by one of several exonucleases with 5′ → 3′ or 3′-gt; 5′ polarity in the presence of the UvrD helicase and the single strand binding protein SSB. An additional central player in MMR is MutL, a molecular matchmaker that mediates proteinprotein interactions and coordinates mismatch recognition with strand incision and degradation (Fig. 1A).The MMR pathway is conserved from E. coli to humans [3]. The essential proteins known to specialize in human MMR are so far limited to MutS and MutL homologs and a 5′ → 3′ exonuclease, ExoI. Eukaryotic MutS and MutL are heterodimers of homologous subunits as opposed to homodimers in bacteria. Human MutSα consists of MSH2 and MSH6, and MutLα consists of MLH1 and PMS2. A strand-specific endonuclease that nicks the daughter strand, like MutH in E. coli, is missing in all eukaryotes and in many bacteria. It is thusCorrespondence and request for material should be addressed to W.Y. e-mail: Wei.Yang@nih.gov phone: (301), 402-4645, fax: (301) 496-0201. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its...

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Transformation of MutL by ATP Binding and Hydrolysis

Cited by 371 publications

References 38 publications

Conformational dynamics of the molecular chaperone Hsp90

Conformational dynamics of the molecular chaperone Hsp90

Modulation of microRNA processing by mismatch repair protein MutLα

Human MutLα: The jack of all trades in MMR is also an endonuclease

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