Affiliations: Genome Technology Branch, National Human Genome
Research Institute, National Institutes of Health, Bethesda, Maryland, 20892
USA | National Center for Biotechnology Information,
National Library of Medicine, National Institutes of Health, Bethesda, Maryland
20894, USA
Note: [] Corresponding author: Genome Technology Branch, National Human
Genome Research Institute, National Institutes of Health, Bethesda, Maryland,
20892 USA, Tel.: +1 301 496 8570, Fax: +1 301402 6858, E-mail:
andy@nhgri.nih.gov
Abstract: The homeodomain is a common structural motif found in many
transcription factors involved in cell fate determination during development.
We have used threading analysis techniques to predict whether the atypical
homeodomain of prospero (pros) family members could form the three-helical
homeodomain structural motif, even though these proteins are not statistically
similar to canonical homeodomains as assessed by BLAST searches. Amino acid
sequences of these divergent homeodomain proteins were threaded through the
X-ray coordinates of the Drosophila engrailed homeodomain protein [23]. The
analysis confirms that the prospero class of homeodomain proteins is indeed
capable of forming the homeodomain structure despite its low degree of sequence
identity to the canonical homeodomain. Energy calculations indicate that the
homeodomain structure is stabilized primarily by hydrophobic interactions
between residues at the helical interfaces. Although the atypical prospero-type
homeodomain shows very little sequence similarity when compared to other
homeodomain proteins, the critical amino acids responsible for maintaining the
three-dimensional structure are highly conserved. A number of other homeodomain
proteins, such as PHO2p from Saccharomyces and Pax6 from human, were also
included in the threading analysis and were shown to be able to form the
engrailed structure, indicating that there are no rigid overall sequence
requirements for the formation of the homeodomain structural motif. Based on
the threading experiments and the subsequent structural alignment, a new amino
acid signature that unambiguously identifies the prospero-type proteins was
deduced.
Keywords: homeodomain, prospero, protein threading, structure prediction
