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discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
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Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
for maintenance.
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
for maintenance.
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
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MetaCyc Polypeptide: MutH

Gene: mutH Accession Numbers: EG10624 (MetaCyc), b2831, ECK2827

Synonyms: mutR, prv

Species: Escherichia coli K-12 substr. MG1655

Component of: MutHLS complex, methyl-directed mismatch repair (extended summary available)

Summary:
MutH is a dGATC endonuclease in the MutHLS complex, the methyl-directed mismatch repair pathway [Welsh87, Au92].

The crystal structure of MutH has been determined in two space groups and solved the structures at 1.7 and 2.3 Å resolution, respectively [Ban98].
Transcription of mutH might be negatively regulated by sigma38 through an intermediate regulator as shown in [Tsui97].

Locations: cytosol

Map Position: [2,967,684 -> 2,968,373]

Molecular Weight of Polypeptide: 25.527 kD (from nucleotide sequence)

Unification Links: ASAP:ABE-0009287 , CGSC:471 , DIP:DIP-10284N , EchoBASE:EB0619 , EcoGene:EG10624 , EcoliWiki:b2831 , Mint:MINT-1542547 , ModBase:P06722 , OU-Microarray:b2831 , PortEco:mutH , PR:PRO_000023323 , Protein Model Portal:P06722 , RefSeq:NP_417308 , RegulonDB:EG10624 , SMR:P06722 , String:511145.b2831 , UniProt:P06722

Relationship Links: InterPro:IN-FAMILY:IPR004230 , InterPro:IN-FAMILY:IPR011335 , InterPro:IN-FAMILY:IPR011337 , PDB:Structure:1AZO , PDB:Structure:2AZO , Pfam:IN-FAMILY:PF02976 , Smart:IN-FAMILY:SM00927

Gene-Reaction Schematic: ?

GO Terms:

Biological Process: GO:0000018 - regulation of DNA recombination Inferred from experiment [Rayssiguier89]
GO:0006298 - mismatch repair Inferred from experiment [Junop03, Lahue89, Glickman80]
GO:0090305 - nucleic acid phosphodiester bond hydrolysis Inferred by computational analysis Inferred from experiment [Welsh87, Junop03, UniProtGOA11a, GOA01]
GO:0006281 - DNA repair Inferred by computational analysis [UniProtGOA11a]
GO:0006304 - DNA modification Inferred by computational analysis [GOA01]
GO:0006974 - cellular response to DNA damage stimulus Inferred by computational analysis [UniProtGOA11a]
Molecular Function: GO:0003677 - DNA binding Inferred from experiment Inferred by computational analysis [GOA01, Junop03]
GO:0004519 - endonuclease activity Inferred from experiment Inferred by computational analysis [UniProtGOA11a, GOA01, Au92, Welsh87]
GO:0005515 - protein binding Inferred from experiment [Polosina09, Mansour01, Hall99]
GO:0043765 - T/G mismatch-specific endonuclease activity Inferred from experiment [Junop03]
GO:0004518 - nuclease activity Inferred by computational analysis [UniProtGOA11a]
GO:0016787 - hydrolase activity Inferred by computational analysis [UniProtGOA11a]
Cellular Component: GO:0032300 - mismatch repair complex Inferred from experiment [Glickman80]
GO:0005737 - cytoplasm Inferred by computational analysis [UniProtGOA11, UniProtGOA11a]
GO:0005829 - cytosol Inferred by computational analysis [DiazMejia09]

MultiFun Terms: information transfer DNA related DNA repair

Credits:
Imported from EcoCyc 16-Sep-2014 by Paley S , SRI International


Subunit of: MutHLS complex, methyl-directed mismatch repair

Species: Escherichia coli K-12 substr. MG1655

Subunit composition of MutHLS complex, methyl-directed mismatch repair = [MutL][MutS][MutH]

Summary:
Mismatched base pairs in Escherichia coli can arise from a number of processes including replication errors, formation of heteroduplexes during recombination events and deamination of 5-methylcytosine. Multiple pathways exist to repair mismatches and one of the challenges these pathways face is in choosing which one of the two bases in the mismatch represents the "correct" DNA and which needs to be repaired. The pathways can be divided into "generalized" and "specific" pathways. Examples of the specific pathways include very short patch (VSP) repair, G:U (MUG) mismatch repair, and MutY based excision repair.

Generalized methyl-directed mismatch repair targets base-base mismatches such as G:T and insertion/deletion loops (IDLs) that cause frameshifts [Schofield03, Au92]. The methyl-directed mismatch repair system (also known as the MutHLS-dependent mismatch repair system) recognizes most base-base mispairs, as well as mismatches involving a small number of nucleotide insertion-deletions [Au92].

The selection of which strand to excise is guided by a methylation system in which newly replicated DNA is unmethylated and therefore sensitive to MutH endonuclease. In the first step MutS binds to the mismatch or IDL and to ATP [Su86, Schofield01]. MutS then recruits MutL and together they activate MutH which then preferentially cleaves the unmethylated strand (the strand with the mismatch) at hemimethylated dGATC sites. The nick at the dGATC site serves as a point of entry for single-stranded DNA binding protein (SSB) and helicase II. Mismatch repair is bidirectional in that the dGATC site can be located on either side of the mismatch and as far as 1kb away. The excision reaction requires either the 3' to 5' exonuclease activity of Exonuclease I or Exonuclease X if the unmethylated GATC site is 3' to the mismatch or the 5' to 3' exonuclease activity of exonuclease VII or RecJ exonuclease if the unmethylated GATC site is 5' to the mismatch [Schofield03, Cooper93]. DNA helicase II (the uvrD gene product) is thought to function to displace the incised strand, rendering it sensitive to attack by the exonuclease [Grilley93]. Hydrolysis thus commences at the dGATC terminus and proceeds to a point beyond the mismatch followed by resynthesis of the excised strand by DNA polymerase III and then ligation by DNA ligase.

Mutation deletion studies of UV radiation-sensitive mutants revealed several genes of importance in the methyl-directed pathway including mutH, mutL, mutS and uvrD, or DNA helicase II. Purification and reconstitution studies [Cooper93] showed that, in addition to these enzymes, single strand DNA-binding protein (SSB), DNA polymerase III, exonuclease I (the sbcB+ gene product), exonuclease VII (the xse+ gene product), RecJ exonuclease, DNA ligase, ATP, the four deoxynucleoside triphosphates and NAD+ are all also required [Grilley93]. MutH was found to be a dGATC endonuclease but only in the course of methyl-directed mismatch activation in the presence of MutL, MutS, ATP and a divalent cation [Welsh87, Au92].

Reviews: [Yang00]

Citations: [Polosina09, Hura13, Acharya03, Wang03a, Junop03, Hall99]

Credits:
Imported from EcoCyc 16-Sep-2014 by Paley S , SRI International


Enzymatic reaction of: methyl-directed mismatch repair

a mismatched DNA base pair <=> a properly matched DNA base pair

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

Reversibility of this reaction is unspecified.

Credits:
Imported from EcoCyc 16-Sep-2014 by Paley S , SRI International

Summary:
The selection of which strand to excise is guided by a methylation system in which newly replicated DNA is unmethylated and therefore sensitive to MutH endonuclease. In the first step MutS binds to the mismatch or IDL and to ATP [Schofield01]. MutS then recruits MutL and together they activate MutH which then preferentially cleaves the unmethylated strand (the strand with the mismatch) at hemimethylated dGATC sites. The nick at the dGATC site serves as a point of entry for single-stranded DNA binding protein (SSB) and helicase II


Sequence Features

Feature Class Location Citations Comment
Cleavage-of-Initial-Methionine 1
[Grafstrom87, UniProt11]
UniProt: Removed.
Chain 2 -> 229
[UniProt09]
UniProt: DNA mismatch repair protein mutH;
Mutagenesis-Variant 28
[UniProt10a]
Alternate sequence: L; UniProt: In TS7; temperature-sensitive;
Extrinsic-Sequence-Variant 58
[UniProt10a]
Alternate sequence: S; UniProt: (in strain: ECOR 67);
Extrinsic-Sequence-Variant 60
[UniProt10a]
Alternate sequence: C; UniProt: (in strain: ECOR 13, ECOR 20, ECOR 26 and ECOR 70);
Extrinsic-Sequence-Variant 64
[UniProt10a]
Alternate sequence: R; UniProt: (in strain: ECOR 50);
Extrinsic-Sequence-Variant 135
[UniProt10a]
Alternate sequence: K; UniProt: (in strain: ECOR 51, ECOR 52, ECOR 57, ECOR 59, ECOR 62 and ECOR 64);
Extrinsic-Sequence-Variant 153
[UniProt10a]
Alternate sequence: R; UniProt: (in strain: ECOR 67);
Extrinsic-Sequence-Variant 155
[UniProt10a]
Alternate sequence: C; UniProt: (in strain: ECOR 35);
Mutagenesis-Variant 157
[UniProt10a]
Alternate sequence: N; UniProt: In TS28; temperature-sensitive;

History:
10/20/97 Gene b2831 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG10624; confirmed by SwissProt match.


References

Acharya03: Acharya S, Foster PL, Brooks P, Fishel R (2003). "The coordinated functions of the E. coli MutS and MutL proteins in mismatch repair." Mol Cell 12(1);233-46. PMID: 12887908

Au92: Au KG, Welsh K, Modrich P (1992). "Initiation of methyl-directed mismatch repair." J Biol Chem 267(17);12142-8. PMID: 1601880

Ban98: Ban C, Yang W (1998). "Structural basis for MutH activation in E.coli mismatch repair and relationship of MutH to restriction endonucleases." EMBO J 17(5);1526-34. PMID: 9482749

Cooper93: Cooper DL, Lahue RS, Modrich P (1993). "Methyl-directed mismatch repair is bidirectional." J Biol Chem 268(16);11823-9. PMID: 8389365

DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114

Glickman80: Glickman BW, Radman M (1980). "Escherichia coli mutator mutants deficient in methylation-instructed DNA mismatch correction." Proc Natl Acad Sci U S A 77(2);1063-7. PMID: 6987663

GOA01: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

Grafstrom87: Grafstrom RH, Hoess RH (1987). "Nucleotide sequence of the Escherichia coli mutH gene." Nucleic Acids Res 15(7);3073-84. PMID: 3031619

Grilley93: Grilley M, Griffith J, Modrich P (1993). "Bidirectional excision in methyl-directed mismatch repair." J Biol Chem 268(16);11830-7. PMID: 8505311

Hall99: Hall MC, Matson SW (1999). "The Escherichia coli MutL protein physically interacts with MutH and stimulates the MutH-associated endonuclease activity." J Biol Chem 274(3);1306-12. PMID: 9880500

Hura13: Hura GL, Tsai CL, Claridge SA, Mendillo ML, Smith JM, Williams GJ, Mastroianni AJ, Alivisatos AP, Putnam CD, Kolodner RD, Tainer JA (2013). "DNA conformations in mismatch repair probed in solution by X-ray scattering from gold nanocrystals." Proc Natl Acad Sci U S A 110(43);17308-13. PMID: 24101514

Junop03: Junop MS, Yang W, Funchain P, Clendenin W, Miller JH (2003). "In vitro and in vivo studies of MutS, MutL and MutH mutants: correlation of mismatch repair and DNA recombination." DNA Repair (Amst) 2(4);387-405. PMID: 12606120

Lahue89: Lahue RS, Au KG, Modrich P (1989). "DNA mismatch correction in a defined system." Science 245(4914);160-4. PMID: 2665076

Mansour01: Mansour CA, Doiron KM, Cupples CG (2001). "Characterization of functional interactions among the Escherichia coli mismatch repair proteins using a bacterial two-hybrid assay." Mutat Res 485(4);331-8. PMID: 11585365

Polosina09: Polosina YY, Mui J, Pitsikas P, Cupples CG (2009). "The Escherichia coli mismatch repair protein MutL recruits the Vsr and MutH endonucleases in response to DNA damage." J Bacteriol 191(12);4041-3. PMID: 19376855

Rayssiguier89: Rayssiguier C, Thaler DS, Radman M (1989). "The barrier to recombination between Escherichia coli and Salmonella typhimurium is disrupted in mismatch-repair mutants." Nature 342(6248);396-401. PMID: 2555716

Schofield01: Schofield MJ, Nayak S, Scott TH, Du C, Hsieh P (2001). "Interaction of Escherichia coli MutS and MutL at a DNA mismatch." J Biol Chem 276(30);28291-9. PMID: 11371566

Schofield03: Schofield MJ, Hsieh P (2003). "DNA mismatch repair: molecular mechanisms and biological function." Annu Rev Microbiol 57;579-608. PMID: 14527292

Su86: Su SS, Modrich P (1986). "Escherichia coli mutS-encoded protein binds to mismatched DNA base pairs." Proc Natl Acad Sci U S A 83(14);5057-61. PMID: 3014530

Tsui97: Tsui HC, Feng G, Winkler ME (1997). "Negative regulation of mutS and mutH repair gene expression by the Hfq and RpoS global regulators of Escherichia coli K-12." J Bacteriol 179(23);7476-87. PMID: 9393714

UniProt09: UniProt Consortium (2009). "UniProt version 15.8 released on 2009-10-01 00:00:00." Database.

UniProt10a: UniProt Consortium (2010). "UniProt version 2010-11 released on 2010-11-02 00:00:00." Database.

UniProt11: UniProt Consortium (2011). "UniProt version 2011-06 released on 2011-06-30 00:00:00." Database.

UniProtGOA11: UniProt-GOA (2011). "Gene Ontology annotation based on the manual assignment of UniProtKB Subcellular Location terms in UniProtKB/Swiss-Prot entries."

UniProtGOA11a: UniProt-GOA (2011). "Gene Ontology annotation based on manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."

Wang03a: Wang H, Yang Y, Schofield MJ, Du C, Fridman Y, Lee SD, Larson ED, Drummond JT, Alani E, Hsieh P, Erie DA (2003). "DNA bending and unbending by MutS govern mismatch recognition and specificity." Proc Natl Acad Sci U S A 100(25);14822-7. PMID: 14634210

Welsh87: Welsh KM, Lu AL, Clark S, Modrich P (1987). "Isolation and characterization of the Escherichia coli mutH gene product." J Biol Chem 262(32);15624-9. PMID: 2824465

Yang00: Yang W (2000). "Structure and function of mismatch repair proteins." Mutat Res 460(3-4);245-56. PMID: 10946232


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Fri Dec 19, 2014, BIOCYC13A.