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Msh6p
Msh6p (Saccharomyces cerevisiae) is product of expression of MSH6 gene.

Msh6p is involved in:

MMR in Saccharomyces cerevisiae
Keywords:


FUNCTION: Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. MSH6 provides substrate-binding and substrate-specificity to the complex. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs. Acts mainly to repair base-base and single insertion-deletion mismatches that occur during replication, but can also repair longer insertion-deletion loops (IDLs), although with decreasing efficiency as the size of the extrahelical loop increases. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. ATP binding and hydrolysis by the MutS alpha complex is crucial for MMR. Both subunits bind ATP, but with differing affinities, and their ATPase kinetics are also very different. MSH6 binds and hydrolyzes ATP rapidly, whereas MSH2 catalyzes ATP at a substantially slower rate. Binding to a mismatched base pair suppresses MSH6-catalyzed ATP hydrolysis, but not the activity of MSH2. ATP binding to both subunits is necessary to trigger a change in MutS alpha interaction with mismatched DNA, converting MutS alpha into a sliding clamp capable of hydrolysis-independent movement along DNA, and also facilitates formation of ternary complexes containing MutS and MutL proteins and the mismatch. May also be involved in resolution of recombination intermediates.

ENZYME REGULATION: Inhibited by Cd(2+).

SUBUNIT: Heterodimer consisting of MSH2-MSH6 (MutS alpha). Forms a ternary complex with MutL alpha (MLH1-PMS1). MutS alpha interacts with proliferating cell nuclear antigen (PCNA/POL30). This interaction is disrupted upon binding of MutS alpha to mismatch DNA.

INTERACTION: P25847:MSH2; NbExp=2; IntAct=EBI-11383, EBI-11352;

SUBCELLULAR LOCATION: Nucleus.

DOMAIN: The PIP box serves as a PCNA(POL30)-recognition and -binding motif.

MISCELLANEOUS: Present with 5330 molecules/cell in log phase SD medium.

SIMILARITY: Belongs to the DNA mismatch repair mutS family.

NCBI GenPept GI number(s): 6320302
Species: Saccharomyces cerevisiae

Links to other databases:

Database ID Link
Uniprot Q03834 Q03834
PFAM: - Q03834 (Link - using uniprot id)
InterPro: - Q03834 (Link - using uniprot id)
CATH: - -
SCOP: - -
PDB: - -


Protein sequence:
MAPATPKTSKTAHFENGSTSSQKKMKQSSLLSFFSKQVPSGTPSKKVQKP
TPATLENTATDKITKNPQGGKTGKLFVDVDEDNDLTIAEETVSTVRSDIM
HSQEPQSDTMLNSNTTEPKSTTTDEDLSSSQSRRNHKRRVNYAESDDDDS
DTTFTAKRKKGKVVDSESDEDEYLPDKNDGDEDDDIADDKEDIKGELAED
SGDDDDLISLAETTSKKKFSYNTSHSSSPFTRNISRDNSKKKSRPNQAPS
RSYNPSHSQPSATSKSSKFNKQNEERYQWLVDERDAQRRPKSDPEYDPRT
LYIPSSAWNKFTPFEKQYWEIKSKMWDCIVFFKKGKFFELYEKDALLANA
LFDLKIAGGGRANMQLAGIPEMSFEYWAAQFIQMGYKVAKVDQRESMLAK
EMREGSKGIVKRELQCILTSGTLTDGDMLHSDLATFCLAIREEPGNFYNE
TQLDSSTIVQKLNTKIFGAAFIDTATGELQMLEFEDDSECTKLDTLMSQV
RPMEVVMERNNLSTLANKIVKFNSAPNAIFNEVKAGEEFYDCDKTYAEII
SSEYFSTEEDWPEVLKSYYDTGKKVGFSAFGGLLYYLKWLKLDKNLISMK
NIKEYDFVKSQHSMVLDGITLQNLEIFSNSFDGSDKGTLFKLFNRAITPM
GKRMMKKWLMHPLLRKNDIESRLDSVDSLLQDITLREQLEITFSKLPDLE
RMLARIHSRTIKVKDFEKVITAFETIIELQDSLKNNDLKGDVSKYISSFP
EGLVEAVKSWTNAFERQKAINENIIVPQRGFDIEFDKSMDRIQELEDELM
EILMTYRKQFKCSNIQYKDSGKEIYTIEIPISATKNVPSNWVQMAANKTY
KRYYSDEVRALARSMAEAKEIHKTLEEDLKNRLCQKFDAHYNTIWMPTIQ
AISNIDCLLAITRTSEYLGAPSCRPTIVDEVDSKTNTQLNGFLKFKSLRH
PCFNLGATTAKDFIPNDIELGKEQPRLGLLTGANAAGKSTILRMACIAVI
MAQMGCYVPCESAVLTPIDRIMTRLGANDNIMQGKSTFFVELAETKKILD
MATNRSLLVVDELGRGGSSSDGFAIAESVLHHVATHIQSLGFFATHYGTL
ASSFKHHPQVRPLKMSILVDEATRNVTFLYKMLEGQSEGSFGMHVASMCG
ISKEIIDNAQIAADNLEHTSRLVKERDLAANNLNGEVVSVPGGLQSDFVR
IAYGDGLKNTKLGSGEGVLNYDWNIKRNVLKSLFSIIDDLQS

Msh6p (Saccharomyces cerevisiae) belongs to following protein families:
References:

Title Authors Journal
Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair. Marsischky GT, Filosi N, Kane MF, Kolodner R Genes Dev Jan. 15, 1996
MSH6, a Saccharomyces cerevisiae protein that binds to mismatches as a heterodimer with MSH2. Iaccarino I, Palombo F, Drummond J, Totty NF, Hsuan JJ, Modrich P, Jiricny J Curr Biol April 1, 1996
The Saccharomyces cerevisiae Msh2 and Msh6 proteins form a complex that specifically binds to duplex oligonucleotides containing mismatched DNA base pairs. Alani E Mol Cell Biol Oct. 1, 1996
The nucleotide sequence of Saccharomyces cerevisiae chromosome IV. Jacq C, Alt-Morbe J, Andre B, Arnold W, Bahr A, Ballesta JP, Bargues M, Baron L, Becker A, Biteau N, Blocker H, Blugeon C, Boskovic J, Brandt P, Bruckner M, Buitrago MJ, Coster F, Delaveau T, del Rey F, Dujon B, Eide LG, Garcia-Cantalejo JM, Goffeau A, Gomez-Peris A, Zaccaria P, et al. Nature May 1, 1997
Microsatellite instability in yeast: dependence on repeat unit size and DNA mismatch repair genes. Sia EA, Kokoska RJ, Dominska M, Greenwell P, Petes TD Mol Cell Biol May 1, 1997
ATP-dependent assembly of a ternary complex consisting of a DNA mismatch and the yeast MSH2-MSH6 and MLH1-PMS1 protein complexes. Habraken Y, Sung P, Prakash L, Prakash S J Biol Chem April 17, 1998
The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations. Flores-Rozas H, Kolodner RD Proc Natl Acad Sci U S A Oct. 13, 1998
Saccharomyces cerevisiae Msh2p and Msh6p ATPase activities are both required during mismatch repair. Studamire B, Quach T, Alani E Mol Cell Biol Dec. 1, 1998
'Saccharomyces cerevisiae MSH2/6 complex interacts with Holliday junctions and facilitates their cleavage by phage resolution enzymes. Marsischky GT, Lee S, Griffith J, Kolodner RD J Biol Chem March 12, 1999
A mutation in the MSH6 subunit of the Saccharomyces cerevisiae MSH2-MSH6 complex disrupts mismatch recognition. Bowers J, Sokolsky T, Quach T, Alani E J Biol Chem June 4, 1999
MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S. cerevisiae. Ni TT, Marsischky GT, Kolodner RD Mol Cell Sept. 1, 1999
Biochemical characterization of the interaction between the Saccharomyces cerevisiae MSH2-MSH6 complex and mispaired bases in DNA. Marsischky GT, Kolodner RD J Biol Chem Sept. 17, 1999
Germ-line msh6 mutations in colorectal cancer families. Kolodner RD, Tytell JD, Schmeits JL, Kane MF, Gupta RD, Weger J, Wahlberg S, Fox EA, Peel D, Ziogas A, Garber JE, Syngal S, Anton-Culver H, Li FP Cancer Res Oct. 15, 1999
Novel dominant mutations in Saccharomyces cerevisiae MSH6. Das Gupta R, Kolodner RD Nat Genet Feb. 1, 2000
Analysis of yeast MSH2-MSH6 suggests that the initiation of mismatch repair can be separated into discrete steps. Bowers J, Tran PT, Liskay RM, Alani E J Mol Biol Sept. 15, 2000
Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex. Flores-Rozas H, Clark D, Kolodner RD Nat Genet Nov. 1, 2000
Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes. Clark AB, Valle F, Drotschmann K, Gary RK, Kunkel TA J Biol Chem Nov. 24, 2000
MSH-MLH complexes formed at a DNA mismatch are disrupted by the PCNA sliding clamp. Bowers J, Tran PT, Joshi A, Liskay RM, Alani E J Mol Biol March 9, 2001
Asymmetric recognition of DNA local distortion. Structure-based functional studies of eukaryotic Msh2-Msh6. Drotschmann K, Yang W, Brownewell FE, Kool ET, Kunkel TA J Biol Chem Dec. 7, 2001
Dominant Saccharomyces cerevisiae msh6 mutations cause increased mispair binding and decreased dissociation from mispairs by Msh2-Msh6 in the presence of ATP. Hess MT, Gupta RD, Kolodner RD J Biol Chem July 12, 2002
Evidence for sequential action of two ATPase active sites in yeast Msh2-Msh6. Drotschmann K, Yang W, Kunkel TA DNA Repair (Amst) Sept. 4, 2002
Transfer of the MSH2.MSH6 complex from proliferating cell nuclear antigen to mispaired bases in DNA. Lau PJ, Kolodner RD J Biol Chem Feb. 3, 2003
Mismatch recognition-coupled stabilization of Msh2-Msh6 in an ATP-bound state at the initiation of DNA repair. Antony E, Hingorani MM Biochemistry July 1, 2003
Global analysis of protein expression in yeast. Ghaemmaghami S, Huh WK, Bower K, Howson RW, Belle A, Dephoure N, O'Shea EK, Weissman JS Nature Oct. 16, 2003
Global analysis of protein localization in budding yeast. Huh WK, Falvo JV, Gerke LC, Carroll AS, Howson RW, Weissman JS, O'Shea EK Nature Oct. 16, 2003
Cadmium inhibits the functions of eukaryotic MutS complexes. Clark AB, Kunkel TA J Biol Chem Dec. 24, 2004
Cadmium inhibits mismatch repair by blocking the ATPase activity of the MSH2-MSH6 complex. Banerjee S, Flores-Rozas H Nucleic Acids Res Jan. 1, 2005
Analysis of the interaction between the Saccharomyces cerevisiae MSH2-MSH6 and MLH1-PMS1 complexes with DNA using a reversible DNA end-blocking system. Mendillo ML, Mazur DJ, Kolodner RD J Biol Chem June 10, 2005
Detection of high-affinity and sliding clamp modes for MSH2-MSH6 by single-molecule unzipping force analysis. Jiang J, Bai L, Surtees JA, Gemici Z, Wang MD, Alani E Mol Cell Dec. 9, 2005
Contribution of Msh2 and Msh6 subunits to the asymmetric ATPase and DNA mismatch binding activities of Saccharomyces cerevisiae Msh2-Msh6 mismatch repair protein. Antony E, Khubchandani S, Chen S, Hingorani MM DNA Repair (Amst) Jan. 3, 2006
Biochemical basis for dominant mutations in the Saccharomyces cerevisiae MSH6 gene. Hess MT, Mendillo ML, Mazur DJ, Kolodner RD Proc Natl Acad Sci U S A Feb. 17, 2006
Inhibition of Msh6 ATPase activity by mispaired DNA induces a Msh2(ATP)-Msh6(ATP) state capable of hydrolysis-independent movement along DNA. Mazur DJ, Mendillo ML, Kolodner RD Mol Cell April 7, 2006
Analysis of the proteins involved in the in vivo repair of base-base mismatches and four-base loops formed during meiotic recombination in the yeast Saccharomyces cerevisiae. Stone JE, Petes TD Genetics July 1, 2006
Multiple functions for the N-terminal region of Msh6. Clark AB, Deterding L, Tomer KB, Kunkel TA Nucleic Acids Res Jan. 1, 2007
Saccharomyces cerevisiae MSH2-MSH3 and MSH2-MSH6 complexes display distinct requirements for DNA binding domain I in mismatch recognition. Lee SD, Surtees JA, Alani E J Mol Biol Jan. 9, 2007
Analysis of phosphorylation sites on proteins from Saccharomyces cerevisiae by electron transfer dissociation (ETD) mass spectrometry. Chi A, Huttenhower C, Geer LY, Coon JJ, Syka JE, Bai DL, Shabanowitz J, Burke DJ, Troyanskaya OG, Hunt DF Proc Natl Acad Sci U S A Jan. 13, 2007
Large-scale phosphorylation analysis of alpha-factor-arrested Saccharomyces cerevisiae. Li X, Gerber SA, Rudner AD, Beausoleil SA, Haas W, Villen J, Elias JE, Gygi SP J Proteome Res March 1, 2007
Specialized mismatch repair function of Glu339 in the Phe-X-Glu motif of yeast Msh6. Holmes SF, Scarpinato KD, McCulloch SD, Schaaper RM, Kunkel TA DNA Repair (Amst) March 1, 2007
Proteome-wide identification of in vivo targets of DNA damage checkpoint kinases. Smolka MB, Albuquerque CP, Chen SH, Zhou H Proc Natl Acad Sci U S A June 19, 2007
Chimeric Saccharomyces cerevisiae Msh6 protein with an Msh3 mispair-binding domain combines properties of both proteins. Shell SS, Putnam CD, Kolodner RD Proc Natl Acad Sci U S A June 26, 2007
A multidimensional chromatography technology for in-depth phosphoproteome analysis. Albuquerque CP, Smolka MB, Payne SH, Bafna V, Eng J, Zhou H Mol Cell Proteomics July 1, 2008

Last modification of this entry: Oct. 6, 2010.

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