The prospero-related homeoproteins Prox1 and Prox2 are the vertebrate
homologs of the Drosophila melanogaster homeodomain-containing protein
Prospero, the founder member of a family of transcription factors which have
been shown to play critical roles in many developmental events. The only
common feature of this family of proteins is the 160-residue C-terminal Homeo-Prospero domain (HPD), which consists of a highly divergent homeodomain (HD)
and an associated Prospero domain (PD) that are essential for sequence-specific DNA binding and the transcriptional activation function of Prospero.
The structure of these two regions consists of a single structural unit (HPD),
in which the Prospero domain region is in position to contribute to DNA
binding and also to mask a defined nuclear export signal that is within the
homeodomain region. The HPD domain coordinately regulates Prospero nuclear
localization and DNA binding specificity. The HPD domain is required for
nearly all the known functions of Prospero, including regulation of nuclear/
cytoplasmic localization, sequence-specific DNA binding, and transcriptional
The HD region does assume an overall fold very similar to homeodomains but
with one striking difference. In the homeodomain structure, the so-called DNA
recognition helix is either at the extreme C-terminus of the protein or leads
into a flexible linker of variable length that connects to another essentially
independent domain. In the HPD domain the recognition helix (α3) connects
the HD region and the PD region as a single structural unit (see <PDB:1MIJ>).
The PD region can be described as a four-helix bundle (α3-α6). At the
extreme C terminus of the HPD domain, a short helix is masked by the PD. When
this helix is unmasked, Prospero is exported from the nucleus [2,3].
The profile we developed covers the entire HPD domain.
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