TFIIIA zinc - fi nger units and others with very similar aa sequences and DNA
binding motifs — Zif268, TTK - 2, YY1 - 3, 1MEY and others — have come to be
known as “ canonical fi ngers. ” Many other known zinc - fi ngers adopt different
aa sequences and DNA binding contacts and have become known as “ non -
standard fi ngers. ” Figure 3 of reference 27 summarizes both types.
Zinc - fi nger aa sequences fold in the presence of zinc to form a compact ββα
domain — two antiparallel β - sheets followed by an α - helix. (Figure 2.21 illus-
trates the three - dimensional structure.) The ending X 5 sequence often has the
amino acid sequence TGEKP forming a fl exible linker between the multiple
zinc fi ngers in a specifi c protein. The zinc ion coordinates tetrahedrally to two
cysteines, lying either in one segment of the β - sheet or in the connector loop
between the two segments of antiparallelβ - sheet, and to two histidines in the
C - terminal end of the α - helical portion of the protein sequence. Zinc coordi-
nation establishes the protein folding pattern, and substituting a residue other
than cys or his at one of the ligand positions usually results in a loss of func-
tion. In binding to DNA, zinc fi ngers have several kinds of contacts, the most
important of these being hydrogen bonding contacts between aa residues on
theα - helix and bases primarily on one strand of ds DNA. This strand is called
theprimary strand. DNA conformational changes that occur on zinc fi nger
binding include an enlarged major groove resulting from a combination of
negative base pair displacement and unwinding of the DNA. Other kinds of
interactions between zinc fi ngers and DNA include hydrophobic and phos-
phate contacts. Most phosphate contacts are made to the primary DNA strand,
the most conserved of these is made through the N δ of the histidine at position
7 of the proteinα - helix (his7). This histidine is also a zinc ligand through its
Nε atom, bringing the phosphate – zinc - fi nger interaction into close proximity
to the DNA strand recognized by the fi nger.
Figure 2.21 Zinc coordination sphere in a zinc - fi nger protein from the synthetic con-
struct corresponding toXenopus Xfi n - 31 domain from PDB: 1ZNF. Visualized using
The PyMOL Molecular Graphics System and ChemDraw Ultra, version 10.0. (Printed
with permission of Delano Scientifi c, LLC and CambridgeSoft Corporation)
Zn(II)cys3 tyr1cys6his19his23asn25PDB: 1ZNFZINC-FINGER PROTEINS 65