STRUCTURAL MOTIFS

OF TRANSCRIPTIONAL
REGULATORS

Bhaskar Ganguly
Ph.D., M.V.Sc., B.V.Sc. & A.H.

The DNA-binding domains of eukaryotic

activators and repressors contain a
variety of structural motifs that bind
specific DNA sequences. The ability of
DNA-binding proteins to bind to specific
DNA sequences commonly results from
non-covalent interactions between atoms
in an helix in the DNA-binding domain
and atoms on the edges of the bases
within a major groove in the DNA.

Helix-turn-helix Motif

Many bacterial repressors are dimeric

proteins in which an helix from each
monomer inserts into a major groove in
the DNA helix; the amino acid side chains
that contact DNA extend from this helix.
This helix is referred to as the
recognition helix or sequence-reading
helix.
The recognition helix is usually supported
in the protein structure in part by
hydrophobic interactions with a second
helix just N-terminal to it.

Zinc-Finger Proteins

A number of different eukaryotic

proteins have regions that fold around a
central Zn2+ ion, producing a compact
domain from a relatively short length of
the polypeptide chain.
Two classes of Zn Finger proteins exist,
not all are transcriptional regulators.

Zinc-Finger Proteins

Two classes:
The C2H2 zinc finger is the most common DNAbinding motif encoded in the genomes of most
other multicellular animals. This motif has a
23- to 26-residue consensus sequence
containing two conserved cysteine (C) and two
conserved histidine (H) residues, whose side
chains bind one Zn2+ ion.
A second type of zinc-finger structure,
designated the C4 zinc finger (because it has
four conserved cysteines in contact with the
Zn2+), is found in 50 human transcription
factors; now commonly called nuclear
receptors.

Leucine-Zipper Proteins
The DNA-binding domains of a large class of
transcription factors contains the hydrophobic
amino acid leucine at every seventh position in
the sequence. These proteins bind to DNA as
dimers, and mutagenesis of the leucines
showed
that
they
were
required
for
dimerization.
The dimeric protein contains two extended
helices that grip the DNA molecule, much like
a pair of scissors, at two adjacent major grooves
separated by about half a turn of the double
helix. The portions of the helices contacting the
DNA include basic residues that interact with
phosphates in the DNA backbone.

Helix-Loop-Helix Proteins
The DNA-binding domain of another
class of dimeric transcription factors
contains a structural motif very similar
to the leucine zipper motif except that a
non-helical loop of the polypeptide
chain separates two -helical regions in
each monomer.

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