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RAD50, an SMC family member with multiple roles in DNA break repair: how does ATP affect function?

Kinoshita E, van der Linden E, Sanchez H, Wyman C - Chromosome Res. (2009)

Bottom Line: All current evidence indicates that ATP binding and hydrolysis cause architectural rearrangements in SMC protein complexes that are important for their functions in organizing DNA.In the case of the MRN complex, the functional significance of ATP binding and hydrolysis are not yet defined.We present some speculation on the role of ATP for function of the MRN complex based on the similarities and differences in the molecular architecture of the Rad50-containing complexes and the SMC complexes condensin and cohesin.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Genetics, Erasmus University Medical Center, Box 2040, 3000 CA Rotterdam, The Netherlands.

ABSTRACT
The protein complex including Mre11, Rad50, and Nbs1 (MRN) functions in DNA double-strand break repair to recognize and process DNA ends as well as signal for cell cycle arrest. Amino acid sequence similarity and overall architecture make Rad50 a member of the structural maintenance of chromosome (SMC) protein family. Like SMC proteins, Rad50 function depends on ATP binding and hydrolysis. All current evidence indicates that ATP binding and hydrolysis cause architectural rearrangements in SMC protein complexes that are important for their functions in organizing DNA. In the case of the MRN complex, the functional significance of ATP binding and hydrolysis are not yet defined. Here we review the data on the ATP-dependent activities of MRN and their possible mechanistic significance. We present some speculation on the role of ATP for function of the MRN complex based on the similarities and differences in the molecular architecture of the Rad50-containing complexes and the SMC complexes condensin and cohesin.

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Related in: MedlinePlus

Illustration of the ATP binding sites at the interface of two ABC ATPase monomers. Only the globular ATPase domains of a generic ABC ATPase, here representing an SMC protein or Rad50, are shown. The Walker A and Walker B motifs are located at the N- and C-terminal ends of the protein, respectively. Domains of the same color are from the same protein or polypeptide chain. ATP binds at the dimer interface, whereby the Walker A and B nucleotide-binding domains contact a highly conserved signature motif (C motif) from a second protein. Two ATPs are shown as there are two possible binding sites formed in a dimer. However, it is not known whether two ATPs can or do bind simultaneously
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Figure 3: Illustration of the ATP binding sites at the interface of two ABC ATPase monomers. Only the globular ATPase domains of a generic ABC ATPase, here representing an SMC protein or Rad50, are shown. The Walker A and Walker B motifs are located at the N- and C-terminal ends of the protein, respectively. Domains of the same color are from the same protein or polypeptide chain. ATP binds at the dimer interface, whereby the Walker A and B nucleotide-binding domains contact a highly conserved signature motif (C motif) from a second protein. Two ATPs are shown as there are two possible binding sites formed in a dimer. However, it is not known whether two ATPs can or do bind simultaneously

Mentions: ATP binding and hydrolysis cause architectural rearrangements in SMC proteins. A functional ATPase is formed in the characteristic SMC structure when intramolecular antiparallel coiled-coil interactions bring the N-terminal Walker A and C-terminal Walker B nucleotide-binding domains together (de Jager et al. 2001b; Haering et al. 2002; Hopfner et al. 2002). These nucleotide-binding domains place SMC proteins in the conserved family of ATP-binding cassette (ABC) ATPases (Hopfner and Tainer 2003; Ye et al. 2004). Although proteins in this family have diverse functions, their ATPase modules share structural and mechanistic properties. ATP binds at a dimer interface whereby the Walker A and B nucleotide-binding domains contact a highly conserved signature motif (C motif) from a second protein (Fig. 3) (Hopfner et al. 2000b). Current evidence supports a picture of functional SMC dimers whereby ATP binding to the two ATPase head domains triggers engagement of two subunits, and subsequent ATP hydrolysis leads to disengagement of this dimer interface (Figs. 2b and c) (Arumugam et al. 2003; Weitzer et al. 2003; Lu et al. 2005).


RAD50, an SMC family member with multiple roles in DNA break repair: how does ATP affect function?

Kinoshita E, van der Linden E, Sanchez H, Wyman C - Chromosome Res. (2009)

Illustration of the ATP binding sites at the interface of two ABC ATPase monomers. Only the globular ATPase domains of a generic ABC ATPase, here representing an SMC protein or Rad50, are shown. The Walker A and Walker B motifs are located at the N- and C-terminal ends of the protein, respectively. Domains of the same color are from the same protein or polypeptide chain. ATP binds at the dimer interface, whereby the Walker A and B nucleotide-binding domains contact a highly conserved signature motif (C motif) from a second protein. Two ATPs are shown as there are two possible binding sites formed in a dimer. However, it is not known whether two ATPs can or do bind simultaneously
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494100&req=5

Figure 3: Illustration of the ATP binding sites at the interface of two ABC ATPase monomers. Only the globular ATPase domains of a generic ABC ATPase, here representing an SMC protein or Rad50, are shown. The Walker A and Walker B motifs are located at the N- and C-terminal ends of the protein, respectively. Domains of the same color are from the same protein or polypeptide chain. ATP binds at the dimer interface, whereby the Walker A and B nucleotide-binding domains contact a highly conserved signature motif (C motif) from a second protein. Two ATPs are shown as there are two possible binding sites formed in a dimer. However, it is not known whether two ATPs can or do bind simultaneously
Mentions: ATP binding and hydrolysis cause architectural rearrangements in SMC proteins. A functional ATPase is formed in the characteristic SMC structure when intramolecular antiparallel coiled-coil interactions bring the N-terminal Walker A and C-terminal Walker B nucleotide-binding domains together (de Jager et al. 2001b; Haering et al. 2002; Hopfner et al. 2002). These nucleotide-binding domains place SMC proteins in the conserved family of ATP-binding cassette (ABC) ATPases (Hopfner and Tainer 2003; Ye et al. 2004). Although proteins in this family have diverse functions, their ATPase modules share structural and mechanistic properties. ATP binds at a dimer interface whereby the Walker A and B nucleotide-binding domains contact a highly conserved signature motif (C motif) from a second protein (Fig. 3) (Hopfner et al. 2000b). Current evidence supports a picture of functional SMC dimers whereby ATP binding to the two ATPase head domains triggers engagement of two subunits, and subsequent ATP hydrolysis leads to disengagement of this dimer interface (Figs. 2b and c) (Arumugam et al. 2003; Weitzer et al. 2003; Lu et al. 2005).

Bottom Line: All current evidence indicates that ATP binding and hydrolysis cause architectural rearrangements in SMC protein complexes that are important for their functions in organizing DNA.In the case of the MRN complex, the functional significance of ATP binding and hydrolysis are not yet defined.We present some speculation on the role of ATP for function of the MRN complex based on the similarities and differences in the molecular architecture of the Rad50-containing complexes and the SMC complexes condensin and cohesin.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Genetics, Erasmus University Medical Center, Box 2040, 3000 CA Rotterdam, The Netherlands.

ABSTRACT
The protein complex including Mre11, Rad50, and Nbs1 (MRN) functions in DNA double-strand break repair to recognize and process DNA ends as well as signal for cell cycle arrest. Amino acid sequence similarity and overall architecture make Rad50 a member of the structural maintenance of chromosome (SMC) protein family. Like SMC proteins, Rad50 function depends on ATP binding and hydrolysis. All current evidence indicates that ATP binding and hydrolysis cause architectural rearrangements in SMC protein complexes that are important for their functions in organizing DNA. In the case of the MRN complex, the functional significance of ATP binding and hydrolysis are not yet defined. Here we review the data on the ATP-dependent activities of MRN and their possible mechanistic significance. We present some speculation on the role of ATP for function of the MRN complex based on the similarities and differences in the molecular architecture of the Rad50-containing complexes and the SMC complexes condensin and cohesin.

Show MeSH
Related in: MedlinePlus