Biology Reference
In-Depth Information
following
100 residues of the protein, is made up of five mixed
b
-strands and
two
a
-helices.
97,101
It is in this second subdomain that residues that have been
deemed important for DNA binding reside (
Fig. 3
).
The structures of the apo- and nucleotide-bound forms of
E. coli
MutL and
hPMS2 are available and they reveal that the relative orientation between
a
/
b
subdomains changes upon nucleotide binding.
97,98,101
Comparison of the
structure of the N-terminal domain of
E. coli
MutL bound to AMPPnP with
those of the nucleotide-bound forms of hMLH1, hPMS2, and yPMS1 unveils
an identical orientation between
a
/
b
subdomains, supporting the idea that
nucleotide binding determines the relative orientation between subdomains.
In
E. coli
MutL, nucleotide binding triggers the association of this domain and
causes the organization of several loops surrounding the nucleotide-binding
site, including the loop connecting helices
a
B and
a
D often referred to as the
ATP lid (
Fig. 3
).
101
Human PMS2 (and its yeast homolog, yPMS1) have a markedly lower
affinity for ATP than other MutL homologs.
98,102,103
While the cause of this
reduced affinity is unclear, the structures of the ATPase domains of hPMS2 and
yPMS1 reveal that these two MutL homologs include unique insertions be-
tween strands
b
9 and
b
10 in the second
a
/
b
subdomain (
Fig. 3
).
98,107
These
insertions could affect the cooperativity between the two
a
/
b
subdomains
and, consequently, alter the ATP- or DNA-binding affinities of these MutL
homologs, though this idea remains to be tested.
F
IG
. 3. Crystal structures of the ATPase domain of MutL. From left to right, ribbon diagrams
of the structures of
E. coli
MutL
AMPPnP, human MLH1
ATP, human PMS2
ATP
g
S, and
Saccharomyces cerevisiae
PMS1
AMPPnP (PDB IDs: 1B63, 3NA3, 1H7U, and 3H4L, respective-
ly). The nucleotides are shown as blue sticks and the nucleotide-binding motifs characteristic of the
GHL family of ATPases are colored in green. The insertions characteristic to the hPMS2 paralog
(PMS1 in yeast) are colored in orange. Residues important for DNA binding are shown as color-
coded sticks and labeled.
