How transcription factors achieve their in vivo specificities is a fun
damental question in biology. For the Homeotic Complex (HOM/Hox) famil
y of homeoproteins, specificity in vive is likely to be in part determ
ined by subtle differences in the DNA binding properties inherent in t
hese proteins. Some of these differences in DNA binding are due to seq
uence differences in the N-terminal arms of HOM/Hox homeodomains. Evid
ence also exists to suggest that cofactors can modify HOM/Hox function
by cooperative DNA binding interactions. The Drosophila homeoprotein
extradenticle (exd) is likely to be one such cofactor. In HOM/Hox prot
eins, both the conserved 'YPWM' peptide motif and the homeodomain are
important for interacting with exd. Although exd provides part of the
answer as to how specificity is achieved, there may be additional cofa
ctors and mechanisms that have yet to be identified.