Histone Fold mediated heterodimerization specifies the selective association of TAF12 paralogs with TFIID and SAGA complexes in Candida albicans.
Transcription initiation in eukaryotes is coordinated by the multisubunit coactivator complexes TFIID and SAGA, which share five core TBP-associated factors (TAFs) that assemble through histone fold (HF) mediated heterodimerization. While, in most organisms, a single TAF12 incorporates in both complexes; however, Candida albicans uniquely encodes two TAF12 paralogs, TAF12 and TAF12L, which associate preferentially with TFIID and SAGA, respectively. The molecular basis and functional consequences of this specialization remain unclear. Here, we demonstrate that Taf12 and Taf12L are functionally non-redundant and show strict complex specificity in vivo, even under conditions where the alternate paralog is depleted. Taf12 associates exclusively with TFIID through Taf4, whereas Taf12L incorporates specifically into SAGA through Ada1. Ectopic expression experiments reveal limited and asymmetric cross-complementation, wherein Taf12L led to partial growth rescue and incorporation into TFIID in absence of Taf12 but not vice versa. Biochemical and genetic analyses further show that the conserved histone fold domains (HFDs) of both paralogs are sufficient for biological function and complex incorporation. In vitro interaction assays uncover intrinsic differences in binding selectivity of Histone fold domains, with HFD-Taf12L displaying strong preference for Ada1, while HFD-Taf12 exhibits more promiscuous binding. Structure-guided mutational analysis identifies the 2-L2 region of the HFD as a major determinant of paralog-specific partner selection. Together, our findings establish that subtle divergence within a conserved histone fold domain underlies the non-redundant integration of Taf12 paralogs into distinct coactivator complexes, revealing a mechanism by which transcriptional machinery can evolve functional specialization through gene duplication.