Biology Reference
In-Depth Information
F
IG
. 2. Architecture of MutL. Ribbon diagrams of the N- and C-terminal domains of
E. coli
MutL (PDB IDs: 1B63 and 1X9Z, respectively), joined by a flexible linker represented by a color-
coded line. The protomers of the dimer are shown in purple and teal with the AMPPnP molecules
bound to the N-terminal domain shown in yellow. The conformational changes imposed by
nucleotide binding are modeled based on the conformational changes indentified by size-exclusion
chromatography and atomic force microscopy data.
97,100,101
The potential semicondensed state is
proposed by analogy to the semicondensed conformations observed in yeast and human MutL
a
.
100
The DNA-binding site is indicated with a gray arrow.
DNA mismatch repair
in vivo
, while the equivalent mutations in hPMS2 have
minimal effect.
105
Collectively, these results suggest that the ATPase activity of
MLH1 is more important than that of PMS2 for normal mismatch repair.
However, it is still unclear how each protomer contributes to the specific
functions of MutL.
Despite the differences between the two protomers, ATP binding stabilizes
the association of the ATPase domains of the two protomers of MutL
a
, in turn
defining the ring-like conformation of the heterodimer.
100,104
A recent study
has shown that yeast MutL
a
diffuses along DNA via a hopping/stepping
mechanism and proposes that yMutL
a
adopts a ring-like architecture to travel
along DNA.
106
The work also suggests that yMutL
a
bypasses obstacles in an
open-ring configuration, underscoring the importance of the nucleotide-
induced conformational changes and the functional asymmetry of the MutL
heterodimer.
A. The ATPase Domain
The structures of the N-terminal regions of
E. coli
, MutL, hMLH1,
hPMS2, and yPMS1, have been determined.
97,98,101,107
This region of MutL
is made up of two
a
/
b
subdomains. The first one, encompassing the N-terminal
200 residues of the protein, is composed of an eight-stranded mixed
b
-sheet
and five
a
-helices, and contains the four conserved motifs characteristic of the
GHL family of ATPases.
29,30
The second
a
/
b
subdomain, encompassing the
