MutS,
a DNA Mismatch Repair Protein of E. coli
David Marcey and Eric Stoffregen
© 2006
I.
Introduction
II. MutS Structure
III. MutS-DNA Interactions
IV. References
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I.
Introduction
The
MutS protein of
Escherichia coli, shown at left in a complex with a
DNA substrate containing
a G-T base mismatch, is a key component of the macromolecular assemblage
responsible for repairing certain types of DNA mutations. MutS
is responsible for recognizing and binding to base pair mismatches,
and recruits other key proteins required
for repair, MutH and MutL, to
the mismatch site.
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II. MutS Structure
MutS
is a large protein (~1600 amino acids) with
numerous alpha
helices and beta
sheets.
Two MutS
monomers
combine to form the functional MutS homodimer.
Each MutS monomer comprises six domains:
- the
helix-turn-helix (HTH) domain is
involved in dimer contacts;
- the
ATPase domain
is responsible for the binding and hydrolysis of ATP;
- the mismatch
domain of the mismatch binding monomer binds
to DNA containing the mismatched bases;
- the core
domain has two regions that from a helical bundle, with two
additional alpha helices extending as levers toward the DNA;
-
the
connector
domain connects the mismatch
domain to the core
domain
- the clamp
domain is involved in DNA binding.
The
DNA double helix
is clasped by the dimer between the
clamp domains and
the mismatch domains
.
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III. MutS-DNA
Interactions
Although
the two MutS monomers are identical, they differ in their orientations
relative to bound DNA. The mismatch-
recognition monomer makes specific contacts to bases in the
region of the mismatch DNA (see below), whereas the non-mismatch-binding
monomer makes only nonspecific contacts with the DNA
backbone.
Initial
DNA recognition is the responsibility of the
clamp domains of
each monomer. These have limited, sequence-independent contacts with
the DNA backbone.
The clamp
domain of the non-mismatch binding monomer
spans the major groove of the DNA,
which is unusually deep due to the kink in the DNA
caused by the base mismatch see below). The clamp
domain of the mismatch-binding monomer contacts
the backbone on either side of the DNA minor
groove.
The clamp domains
present a positively charged surface
to the DNA backbone, allowing protein-phosphate
electrostatic bonding
(please allow time for surface view to load).
The
mismatch-binding domain of the mismatch-recognition
monomer contacts the minor groove of the DNA.
Three specific
interactions between residues of the mismatch-binding
domain and
the DNA allow
the recognition of the G
- T base mismatch:
- glu38
forms hydrogen bonds to the thymine of
the base mismatch and to a neighboring guanine
adjacent to the guanine
of the mismatch;
- asp35
forms a hydrogen bond with the guanine
of the mismatch;
- phe36
stacks with the thymine
of the
mismatch.
Please repeat
the illustration of these interactions, noting that the minor groove
of the DNA is widened by the kink caused by the base mismatch. This
permits the negatively charged sidechains of glu38
and asp35 to
contact bases in the minor groove without electrostatic repulsion
by the negatively charged DNA backbone.
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IV. References
Lamers, M. H.,
Perrakis, A., Enzlin, J. H., Winterwerp, H. H., De Wind, N., Sixma,
T. K.: The Crystal Structure of DNA Mismatch Repair Protein Muts Binding
to a G x T Mismatch. Nature 407: 711-717 (2000).
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