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MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta.

Publication ,  Journal Article
Iyer, RR; Pluciennik, A; Genschel, J; Tsai, M-S; Beese, LS; Modrich, P
Published in: J Biol Chem
April 9, 2010

MutSbeta (MSH2-MSH3) mediates repair of insertion-deletion heterologies but also triggers triplet repeat expansions that cause neurological diseases. Like other DNA metabolic activities, MutSbeta interacts with proliferating cell nuclear antigen (PCNA) via a conserved motif (QXX(L/I)XXFF). We demonstrate that MutSbeta-PCNA complex formation occurs with an affinity of approximately 0.1 microM and a preferred stoichiometry of 1:1. However, up to 20% of complexes are multivalent under conditions where MutSbeta is in molar excess over PCNA. Conformational studies indicate that the two proteins associate in an end-to-end fashion in solution. Surprisingly, mutation of the PCNA-binding motif of MutSbeta not only abolishes PCNA binding, but unlike MutSalpha, also dramatically attenuates MutSbeta-MutLalpha interaction, MutLalpha endonuclease activation, and bidirectional mismatch repair. As predicted by these findings, PCNA competes with MutLalpha for binding to MutSbeta, an effect that is blocked by the cell cycle regulator p21(CIP1). We propose that MutSbeta-MutLalpha interaction is mediated in part by residues ((L/I)SRFF) embedded within the MSH3 PCNA-binding motif. To our knowledge this is the first case where residues important for PCNA binding also mediate interaction with a second protein. These findings also indicate that MutSbeta- and MutSalpha-initiated repair events differ in fundamental ways.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

April 9, 2010

Volume

285

Issue

15

Start / End Page

11730 / 11739

Location

United States

Related Subject Headings

  • Sequence Homology, Amino Acid
  • Proliferating Cell Nuclear Antigen
  • Mutation
  • MutL Proteins
  • Molecular Sequence Data
  • Insecta
  • Humans
  • DNA Repair Enzymes
  • DNA Repair
  • Cyclin-Dependent Kinase Inhibitor p21
 

Citation

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Iyer, R. R., Pluciennik, A., Genschel, J., Tsai, M.-S., Beese, L. S., & Modrich, P. (2010). MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta. J Biol Chem, 285(15), 11730–11739. https://doi.org/10.1074/jbc.M110.104125
Iyer, Ravi R., Anna Pluciennik, Jochen Genschel, Miaw-Sheue Tsai, Lorena S. Beese, and Paul Modrich. “MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta.J Biol Chem 285, no. 15 (April 9, 2010): 11730–39. https://doi.org/10.1074/jbc.M110.104125.
Iyer RR, Pluciennik A, Genschel J, Tsai M-S, Beese LS, Modrich P. MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta. J Biol Chem. 2010 Apr 9;285(15):11730–9.
Iyer, Ravi R., et al. “MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta.J Biol Chem, vol. 285, no. 15, Apr. 2010, pp. 11730–39. Pubmed, doi:10.1074/jbc.M110.104125.
Iyer RR, Pluciennik A, Genschel J, Tsai M-S, Beese LS, Modrich P. MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta. J Biol Chem. 2010 Apr 9;285(15):11730–11739.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

April 9, 2010

Volume

285

Issue

15

Start / End Page

11730 / 11739

Location

United States

Related Subject Headings

  • Sequence Homology, Amino Acid
  • Proliferating Cell Nuclear Antigen
  • Mutation
  • MutL Proteins
  • Molecular Sequence Data
  • Insecta
  • Humans
  • DNA Repair Enzymes
  • DNA Repair
  • Cyclin-Dependent Kinase Inhibitor p21