Acquisition of a Leucine Zipper Motif as a Mechanism of Antimorphy for an Allele of the Drosophila Hox Gene Sex Combs Reduced

In 1932, Müller first used the term "antimorphic" to describe mutant alleles that have an effect that is antagonistic to that of the wild-type allele from which they were derived. In a previous characterization of mutant alleles of the Drosophila melanogaster Hox gene, Sex combs reduced (Scr), we identified the missense, antimorphic allele Scr(14), which is a Ser10-to-Leu change in the N-terminally located, bilateran-specific octapeptide motif. Here we propose that the cause of Scr(14) antimorphy is the acquisition of a leucine zipper oligomerization motif spanning the octapeptide motif and adjacently located protostome-specific LASCY motif. Analysis of the primary and predicted secondary structures of the SCR N-terminus suggests that while the SCR(+) encodes a short, α-helical region containing one putative heptad repeat, the same region in SCR(14) encodes a longer, α-helical region containing two putative heptad repeats. In addition, in vitro cross-linking assays demonstrated strong oligomerization of SCR(14) but not SCR(+). For in vivo sex comb formation, we observed reciprocal inhibition of endogenous SCR(+) and SCR(14) activity by ectopic expression of truncated SCR(14) and SCR(+) peptides, respectively. The acquisition of an oligomerization domain in SCR(14) presents a novel mechanism of antimorphy relative to the dominant negative mechanism, which maintains oligomerization between the wild-type and mutant protein subunits.