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DNA mismatch repair
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PDB id
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1b62
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* Residue conservation analysis
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Gene Ontology (GO) functional annotation
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Biological process
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mismatch repair
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1 term
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Biochemical function
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ATP binding
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2 terms
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DOI no:
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Cell
97:85-97
(1999)
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PubMed id:
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Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair.
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C.Ban,
M.Junop,
W.Yang.
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ABSTRACT
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The MutL DNA mismatch repair protein has recently been shown to be an ATPase and
to belong to an emerging ATPase superfamily that includes DNA topoisomerase II
and Hsp90. We report here the crystal structures of a 40 kDa ATPase fragment of
E. coli MutL (LN40) complexed with a substrate analog, ADPnP, and with product
ADP. More than 60 residues that are disordered in the apoprotein structure
become ordered and contribute to both ADPnP binding and dimerization of LN40.
Hydrolysis of ATP, signified by subsequent release of the gamma-phosphate,
releases two key loops and leads to dissociation of the LN40 dimer. Dimerization
of the LN40 region is required for and is the rate-limiting step in ATP
hydrolysis by MutL. The ATPase activity of MutL is stimulated by DNA and likely
acts as a switch to coordinate DNA mismatch repair.
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Selected figure(s)
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Figure 7.
Figure 7. Molecular Surface of the LN40–ADPnP Complex and
Interaction between MutL and DNAThe molecular surface viewed
from front (a), bottom (b), and top (c). Each interface is
labeled with a potential counterpart. Electropotential, positive
(blue) or negative (red), is also mapped onto the molecular
surface. (d) DNA binding by MutL and the R266E mutant MutL. (e)
The ATPase activity of MutL and R266E in response to DNA.
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Figure 8.
Figure 8. Mutations of hMLH1 Found in the HNPCC
KindredFourteen hMLH1 mutations are mapped onto the MutL
structure based on the sequence homology. Protein is shown in
green ribbon diagram and ATP moiety in light yellow sticks. The
original side chains of MutL are shown in ball and stick and
labeled in blue. Mutations of hMLH1 that would affect ATPase
activity are labeled in red, and others are labeled in magenta.
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The above figures are
reprinted
by permission from Cell Press:
Cell
(1999,
97,
85-97)
copyright 1999.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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| |
PubMed id
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Reference
|
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|
|
A.N.Schorzman,
L.Perera,
J.M.Cutalo-Patterson,
L.C.Pedersen,
L.G.Pedersen,
T.A.Kunkel,
and
K.B.Tomer
(2011).
Modeling of the DNA-binding site of yeast Pms1 by mass spectrometry.
|
| |
DNA Repair (Amst), 10,
454-465.
|
|
|
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|
|
C.Duvernay,
L.Coulange,
B.Dutilh,
V.Dubois,
C.Quentin,
and
C.Arpin
(2011).
Duplication of the chromosomal blaSHV-11 gene in a clinical hypermutable strain of Klebsiella pneumoniae.
|
| |
Microbiology, 157,
496-503.
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|
C.Galles,
R.L.Gomez,
and
C.P.Spampinato
(2011).
PMS1 from Arabidopsis thaliana: optimization of protein overexpression in Escherichia coli.
|
| |
Mol Biol Rep, 38,
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G.E.Karagöz,
A.M.Duarte,
H.Ippel,
C.Uetrecht,
T.Sinnige,
M.van Rosmalen,
J.Hausmann,
A.J.Heck,
R.Boelens,
and
S.G.Rüdiger
(2011).
N-terminal domain of human Hsp90 triggers binding to the cochaperone p23.
|
| |
Proc Natl Acad Sci U S A, 108,
580-585.
|
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|
H.Iino,
K.Kim,
A.Shimada,
R.Masui,
S.Kuramitsu,
and
K.Fukui
(2011).
Characterization of C- and N-terminal domains of Aquifex aeolicus MutL endonuclease: N-terminal domain stimulates the endonuclease activity of C-terminal domain in a zinc-dependent manner.
|
| |
Biosci Rep, 31,
309-322.
|
|
|
|
|
|
|
J.King-Scott,
P.V.Konarev,
S.Panjikar,
R.Jordanova,
D.I.Svergun,
and
P.A.Tucker
(2011).
Structural characterization of the multidomain regulatory protein Rv1364c from Mycobacterium tuberculosis.
|
| |
Structure, 19,
56-69.
|
|
|
|
|
|
|
M.D.Szczelkun
(2011).
Translocation, switching and gating: potential roles for ATP in long-range communication on DNA by Type III restriction endonucleases.
|
| |
Biochem Soc Trans, 39,
589-594.
|
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|
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J.Mauris,
and
T.C.Evans
(2010).
A human PMS2 homologue from Aquifex aeolicus stimulates an ATP-dependent DNA helicase.
|
| |
J Biol Chem, 285,
11087-11092.
|
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|
J.Park,
Y.Jeon,
D.In,
R.Fishel,
C.Ban,
and
J.B.Lee
(2010).
Single-molecule analysis reveals the kinetics and physiological relevance of MutL-ssDNA binding.
|
| |
PLoS One, 5,
e15496.
|
|
|
|
|
|
|
K.Fukui
(2010).
DNA mismatch repair in eukaryotes and bacteria.
|
| |
J Nucleic Acids, 2010,
0.
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M.C.Pillon,
J.J.Lorenowicz,
M.Uckelmann,
A.D.Klocko,
R.R.Mitchell,
Y.S.Chung,
P.Modrich,
G.C.Walker,
L.A.Simmons,
P.Friedhoff,
and
A.Guarné
(2010).
Structure of the endonuclease domain of MutL: unlicensed to cut.
|
| |
Mol Cell, 39,
145-151.
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PDB codes:
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M.E.Arana,
S.F.Holmes,
J.M.Fortune,
A.F.Moon,
L.C.Pedersen,
and
T.A.Kunkel
(2010).
Functional residues on the surface of the N-terminal domain of yeast Pms1.
|
| |
DNA Repair (Amst), 9,
448-457.
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|
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PDB code:
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R.Morita,
S.Nakane,
A.Shimada,
M.Inoue,
H.Iino,
T.Wakamatsu,
K.Fukui,
N.Nakagawa,
R.Masui,
and
S.Kuramitsu
(2010).
Molecular mechanisms of the whole DNA repair system: a comparison of bacterial and eukaryotic systems.
|
| |
J Nucleic Acids, 2010,
179594.
|
|
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|
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|
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S.M.Offer,
Q.Pan-Hammarström,
L.Hammarström,
and
R.S.Harris
(2010).
Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.
|
| |
PLoS One, 5,
e12260.
|
|
|
|
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|
|
V.E.Cotton,
E.R.Hoffmann,
and
R.H.Borts
(2010).
Distinct regulation of Mlh1p heterodimers in meiosis and mitosis in Saccharomyces cerevisiae.
|
| |
Genetics, 185,
459-467.
|
|
|
|
|
|
|
F.J.López de Saro
(2009).
Regulation of interactions with sliding clamps during DNA replication and repair.
|
| |
Curr Genomics, 10,
206-215.
|
|
|
|
|
|
|
J.Mauris,
and
T.C.Evans
(2009).
Adenosine triphosphate stimulates Aquifex aeolicus MutL endonuclease activity.
|
| |
PLoS One, 4,
e7175.
|
|
|
|
|
|
|
L.S.Li,
J.C.Morales,
M.Veigl,
D.Sedwick,
S.Greer,
M.Meyers,
M.Wagner,
R.Fishel,
and
D.A.Boothman
(2009).
DNA mismatch repair (MMR)-dependent 5-fluorouracil cytotoxicity and the potential for new therapeutic targets.
|
| |
Br J Pharmacol, 158,
679-692.
|
|
|
|
|
|
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M.Clyne,
J.Offman,
S.Shanley,
J.D.Virgo,
M.Radulovic,
Y.Wang,
A.Ardern-Jones,
R.Eeles,
E.Hoffmann,
and
V.P.Yu
(2009).
The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome.
|
| |
Br J Cancer, 100,
376-380.
|
|
|
|
|
|
|
M.L.Mendillo,
V.V.Hargreaves,
J.W.Jamison,
A.O.Mo,
S.Li,
C.D.Putnam,
V.L.Woods,
and
R.D.Kolodner
(2009).
A conserved MutS homolog connector domain interface interacts with MutL homologs.
|
| |
Proc Natl Acad Sci U S A, 106,
22223-22228.
|
|
|
|
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|
|
R.J.Heinze,
L.Giron-Monzon,
A.Solovyova,
S.L.Elliot,
S.Geisler,
C.G.Cupples,
B.A.Connolly,
and
P.Friedhoff
(2009).
Physical and functional interactions between Escherichia coli MutL and the Vsr repair endonuclease.
|
| |
Nucleic Acids Res, 37,
4453-4463.
|
|
|
|
|
|
|
W.Sjursen,
I.Bjørnevoll,
L.F.Engebretsen,
K.Fjelland,
T.Halvorsen,
and
H.E.Myrvold
(2009).
A homozygote splice site PMS2 mutation as cause of Turcot syndrome gives rise to two different abnormal transcripts.
|
| |
Fam Cancer, 8,
179-186.
|
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|
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|
|
A.Demogines,
A.Wong,
C.Aquadro,
and
E.Alani
(2008).
Incompatibilities involving yeast mismatch repair genes: a role for genetic modifiers and implications for disease penetrance and variation in genomic mutation rates.
|
| |
PLoS Genet, 4,
e1000103.
|
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|
|
D.R.Southworth,
and
D.A.Agard
(2008).
Species-dependent ensembles of conserved conformational states define the Hsp90 chaperone ATPase cycle.
|
| |
Mol Cell, 32,
631-640.
|
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|
|
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|
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E.J.Sacho,
F.A.Kadyrov,
P.Modrich,
T.A.Kunkel,
and
D.A.Erie
(2008).
Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha.
|
| |
Mol Cell, 29,
112-121.
|
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|
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G.Plotz,
J.Raedle,
A.Spina,
C.Welsch,
A.Stallmach,
S.Zeuzem,
and
C.Schmidt
(2008).
Evaluation of the MLH1 I219V alteration in DNA mismatch repair activity and ulcerative colitis.
|
| |
Inflamm Bowel Dis, 14,
605-611.
|
|
|
|
|
|
|
K.Fukui,
M.Nishida,
N.Nakagawa,
R.Masui,
and
S.Kuramitsu
(2008).
Bound nucleotide controls the endonuclease activity of mismatch repair enzyme MutL.
|
| |
J Biol Chem, 283,
12136-12145.
|
|
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|
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|
|
M.K.Korhonen,
E.Vuorenmaa,
and
M.Nyström
(2008).
The first functional study of MLH3 mutations found in cancer patients.
|
| |
Genes Chromosomes Cancer, 47,
803-809.
|
|
|
|
|
|
|
N.D.Thomsen,
and
J.M.Berger
(2008).
Structural frameworks for considering microbial protein- and nucleic acid-dependent motor ATPases.
|
| |
Mol Microbiol, 69,
1071-1090.
|
|
|
|
|
|
|
R.M.Wynn,
M.Kato,
J.L.Chuang,
S.C.Tso,
J.Li,
and
D.T.Chuang
(2008).
Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity.
|
| |
J Biol Chem, 283,
25305-25315.
|
|
|
PDB codes:
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|
|
S.Besier,
J.Zander,
B.C.Kahl,
P.Kraiczy,
V.Brade,
and
T.A.Wichelhaus
(2008).
The thymidine-dependent small-colony-variant phenotype is associated with hypermutability and antibiotic resistance in clinical Staphylococcus aureus isolates.
|
| |
Antimicrob Agents Chemother, 52,
2183-2189.
|
|
|
|
|
|
|
D.E.Dollins,
J.J.Warren,
R.M.Immormino,
and
D.T.Gewirth
(2007).
Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones.
|
| |
Mol Cell, 28,
41-56.
|
|
|
PDB codes:
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|
|
J.Gorman,
A.Chowdhury,
J.A.Surtees,
J.Shimada,
D.R.Reichman,
E.Alani,
and
E.C.Greene
(2007).
Dynamic basis for one-dimensional DNA scanning by the mismatch repair complex Msh2-Msh6.
|
| |
Mol Cell, 28,
359-370.
|
|
|
|
|
|
|
K.Takahashi,
N.Yoshida,
N.Murakami,
K.Kawata,
H.Ishizaki,
M.Tanaka-Okamoto,
J.Miyoshi,
A.R.Zinn,
H.Shime,
and
N.Inoue
(2007).
Dynamic regulation of p53 subnuclear localization and senescence by MORC3.
|
| |
Mol Biol Cell, 18,
1701-1709.
|
|
|
|
|
|
|
M.Kato,
J.Li,
J.L.Chuang,
and
D.T.Chuang
(2007).
Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol.
|
| |
Structure, 15,
992.
|
|
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PDB codes:
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|
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T.Davidsen,
H.K.Tuven,
M.Bjørås,
E.A.Rødland,
and
T.Tønjum
(2007).
Genetic interactions of DNA repair pathways in the pathogen Neisseria meningitidis.
|
| |
J Bacteriol, 189,
5728-5737.
|
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|
|
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|
|
W.Yang
(2007).
Human MutLalpha: the jack of all trades in MMR is also an endonuclease.
|
| |
DNA Repair (Amst), 6,
135-139.
|
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|
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|
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A.B.Robertson,
S.R.Pattishall,
E.A.Gibbons,
and
S.W.Matson
(2006).
MutL-catalyzed ATP hydrolysis is required at a post-UvrD loading step in methyl-directed mismatch repair.
|
| |
J Biol Chem, 281,
19949-19959.
|
|
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|
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|
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A.K.Shiau,
S.F.Harris,
D.R.Southworth,
and
D.A.Agard
(2006).
Structural Analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements.
|
| |
Cell, 127,
329-340.
|
|
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PDB codes:
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A.Robertson,
S.R.Pattishall,
and
S.W.Matson
(2006).
The DNA binding activity of MutL is required for methyl-directed mismatch repair in Escherichia coli.
|
| |
J Biol Chem, 281,
8399-8408.
|
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|
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|
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F.J.López de Saro,
M.G.Marinus,
P.Modrich,
and
M.O'Donnell
(2006).
The beta sliding clamp binds to multiple sites within MutL and MutS.
|
| |
J Biol Chem, 281,
14340-14349.
|
|
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|
|
|
|
G.Plotz,
C.Welsch,
L.Giron-Monzon,
P.Friedhoff,
M.Albrecht,
A.Piiper,
R.M.Biondi,
T.Lengauer,
S.Zeuzem,
and
J.Raedle
(2006).
Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair.
|
| |
Nucleic Acids Res, 34,
6574-6586.
|
|
|
|
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|
|
G.Plotz,
S.Zeuzem,
and
J.Raedle
(2006).
DNA mismatch repair and Lynch syndrome.
|
| |
J Mol Histol, 37,
271-283.
|
|
|
|
|
|
|
K.D.Corbett,
and
J.M.Berger
(2006).
Structural basis for topoisomerase VI inhibition by the anti-Hsp90 drug radicicol.
|
| |
Nucleic Acids Res, 34,
4269-4277.
|
|
|
PDB code:
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|
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|
|
K.Richter,
S.Moser,
F.Hagn,
R.Friedrich,
O.Hainzl,
M.Heller,
S.Schlee,
H.Kessler,
J.Reinstein,
and
J.Buchner
(2006).
Intrinsic inhibition of the Hsp90 ATPase activity.
|
| |
J Biol Chem, 281,
11301-11311.
|
|
|
PDB code:
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|
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|
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|
|
|
L.H.Pearl,
and
C.Prodromou
(2006).
Structure and mechanism of the Hsp90 molecular chaperone machinery.
|
| |
Annu Rev Biochem, 75,
271-294.
|
|
|
|
|
|
|
M.M.Ali,
S.M.Roe,
C.K.Vaughan,
P.Meyer,
B.Panaretou,
P.W.Piper,
C.Prodromou,
and
L.H.Pearl
(2006).
Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex.
|
| |
Nature, 440,
1013-1017.
|
|
|
PDB codes:
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|
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|
|
|
R.Ahrends,
J.Kosinski,
D.Kirsch,
L.Manelyte,
L.Giron-Monzon,
L.Hummerich,
O.Schulz,
B.Spengler,
and
P.Friedhoff
(2006).
Identifying an interaction site between MutH and the C-terminal domain of MutL by crosslinking, affinity purification, chemical coding and mass spectrometry.
|
| |
Nucleic Acids Res, 34,
3169-3180.
|
|
|
|
|
|
|
S.H.Jun,
T.G.Kim,
and
C.Ban
(2006).
DNA mismatch repair system. Classical and fresh roles.
|
| |
FEBS J, 273,
1609-1619.
|
|
|
|
|
|
|
S.W.Matson,
and
A.B.Robertson
(2006).
The UvrD helicase and its modulation by the mismatch repair protein MutL.
|
| |
Nucleic Acids Res, 34,
4089-4097.
|
|
|
|
|
|
|
T.Davidsen,
and
T.Tønjum
(2006).
Meningococcal genome dynamics.
|
| |
Nat Rev Microbiol, 4,
11-22.
|
|
|
|
|
|
|
A.Bracher,
and
F.U.Hartl
(2005).
Towards a complete structure of Hsp90.
|
| |
Structure, 13,
501-502.
|
|
|
|
|
|
|
A.Giraldo,
A.Gómez,
G.Salguero,
H.García,
F.Aristizábal,
O.Gutiérrez,
L.A.Angel,
J.Padrón,
C.Martínez,
H.Martínez,
O.Malaver,
L.Flórez,
and
R.Barvo
(2005).
MLH1 and MSH2 mutations in Colombian families with hereditary nonpolyposis colorectal cancer (Lynch syndrome)--description of four novel mutations.
|
| |
Fam Cancer, 4,
285-290.
|
|
|
|
|
|
|
A.L.Prunier,
and
R.Leclercq
(2005).
Role of mutS and mutL genes in hypermutability and recombination in Staphylococcus aureus.
|
| |
J Bacteriol, 187,
3455-3464.
|
|
|
|
|
|
|
D.E.Dollins,
R.M.Immormino,
and
D.T.Gewirth
(2005).
Structure of unliganded GRP94, the endoplasmic reticulum Hsp90. Basis for nucleotide-induced conformational change.
|
| |
J Biol Chem, 280,
30438-30447.
|
|
|
PDB codes:
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|
|
E.S.Hong,
A.Yeung,
P.Funchain,
M.M.Slupska,
and
J.H.Miller
(2005).
Mutants with temperature-sensitive defects in the Escherichia coli mismatch repair system: sensitivity to mispairs generated in vivo.
|
| |
J Bacteriol, 187,
840-846.
|
|
|
|
|
|
|
H.N.Trong,
A.L.Prunier,
and
R.Leclercq
(2005).
Hypermutable and fluoroquinolone-resistant clinical isolates of Staphylococcus aureus.
|
| |
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S.C.Sinha,
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M.C.Hall,
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G.Plotz,
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Genetics, 160,
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Proc Natl Acad Sci U S A, 98,
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M.S.Junop,
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PDB code:
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Cell, 101,
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PDB codes:
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PDB codes:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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