When p53 function is reduced due to mutations
that often occur prior to cancer formation, DNA repair capabilities are
reduced: p53 can no longer aid in DNA restoration or arrest the cell cycle
to provide time for other factors to correct DNA damage. Apoptosis would normally
remove cells with damaged DNA; however, loss of p53 function also results
in a decreased ability of the cell to undergo apoptosis. Without apoptosis,
the cell continues to proliferate despite severe DNA damage, promoting cancer
formation. Mutations in p53 along with mutations in other proto-oncogenes
and tumor-suppressor genes are unfortunately very common and often result
in cancer. Because of the multiple roles of p53, loss of p53 function in cells
is deleterious and unfortunately very common in cancer (Alberts et al,
Please reload the image after each section by
pressing this button:
The core domains each consist of two anti-parallel beta-sheets that contain four to five beta-strands
. The core domains also contain a loop-sheet-helix motif
across an extended hydrophobic core, forming a beta sandwich. Two large
loops at the edge of the sandwich are bound together by a tetrehedrally coordinated
. The helix and loop bind to the major
groove and contact the edges of base pairs. Both structures contact the DNA
backbone. The amino terminus of each subunit consists of five tightly packed
beta strands. The carboxyl terminus consists of four beta strands connected
by short 5-11 residue loops. .
Please reload the image by pressing this button:
In the major groove
, Lys120 from loop L1 hydrogen bonds with G8 while Cys277 hydrogen bonds with
C9. The most important
major grove contact is between Arg280 from the a-helix to G10. In addition, Arg280 is stabilized by a salt bridge with
the Asp281 carboxylate.
In the minor groove
, Arg248from loop L3 is packed against the DNA backbone because
of the local compression of the minor groove. At this region, the minor groove
width is 9.3Å rather than the normal 11.5Å of B-DNA. This probably
results from the high A-T content of the sequence. A water molecule makes
hydrogen bonds between Arg248 and G13.
DNA backbone contacts
occur between the phosphate of G10 and Ser241 from the L3 loop and
Ala276 from the
loop-sheet-helix. The phosphate of T11 is bound to Arg273. Arg273 is also involved in multiple interactions including
a salt bridge with the carboxylate of Asp281. In addition, Lys120 contacts the O3’ of T6 while Arg283 contacts the phosphate of G7.
The most frequently mutated residues are Arg-175, Arg-248, Arg-249, Arg-282, and
Gly-245. Arg-175 bridges portions of the L2
and L3 loops, stabilizing them
. Arg-175 mutants unfold portions of
the core domain, creating structural defects that allow accessibility of
proteases to the N-terminus (Cho et al, 1994). Arg-273 and Arg-280 are
mutations in the DNA binding domain and limit p53 DNA binding by disrupting
phosphate backbone linkages
Almog N, Rotter V. (1998) An insight
into the life of p53: a protein coping with many function! Biochimica et
Biophisica Acta. 1378: R43-R54.
Bálint É, Vousden
KH. (2001) Activation and activities of the p53 tumor suppressor protein.
British Journal of Cancer 85(12): 1813-1823.
Cho Y, Gorina S, Jeffrey PD, Pavletich
NP. (1994) Crystal structure of a p53 tumor suppressor-DNA complex: understanding
tumorigenic mutations. Science 265: 346-355.
Donehower LA, Harvey M, Slagle
BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A (1992) Mice deficient
for p53 are developmentally normal but susceptible to spontaneous tumours.
Walker DR, Bond JP, Tarone RE,
Harris CC, Makalowski W, Boguski MS, Greenblatt MS. (1999) Evolutionary
conservation and somatic mutation hotspot maps of p53: correlation
with p53 protein structural and functional features. Oncogene 19:211-218.