Ataxin-7 (ATXN7) is a component of mammalian STAGA (SPT3-TAF9-ADA-GCN5 acetyltransferase) transcription co-activator complex []. Ataxin-7 associates with microtubules and stabilises the cytoskeletal network []. Normal ATXN7 contains 4-35 CAG repeats, whereas pathogenic variants show an expansion of 36-306 repeats of this CAG repeat encoding polyglutamine (polyQ) that causes spinocerebellar ataxia 7 (SCA7), a neurodegenerative disorder characterised by cerebellar ataxia associated with progressive macular dystrophy []. Polyglutamine-expanded ATXN7 inhibits STAGA histone acetyltransferase activity [, ].
SAGA (Spt-Ada-Gcn5 acetyltransferase), a coactivator complex involved inchromatin remodelling, harbours both histone acetylation and deubiquitinationactivities. SAGA-associated factor 73 (Sgf734/ATXN7) and Ataxin-7-like protein 3 (ATXN7L3), two subunits of the SAGA deubiquitinationmodule, contain an ~50-residue SCA7 domain characterised by an atypical zinc-finger (Znf) with a Cys-X(9,10)-Cys-X(5)-Cys-X(2)-His motif and a long sequence insertion between the first two zinccoordinating residues.The SCA7 domain is found exclusively in members of theATXN7 gene family, which includes two distinct subunits of SAGA complexes:ATXN7 and ATXN7L3 orthologues. The analysis of multiple alignments highlightsthe consensus signature for the SCA7 domain, encompassing the putative zinc-coordinating residues, but also reveals the distinct features of the twoproteins. Marked differences are found mostly in the carboxy-terminal of thedomain, suggesting that divergent evolution of the SCA7 Znf domain occurred inorder to achieve specific functions in the SAGA complex. Both SCA7 domainscontain disordered regions, albeit not in the same region. Whereas the firstand last 10 residues of ATXN7-SCA7 are not folded, the N-terminal region of ATXN7L3-SCA7 is well structured and thelast 30 residues of this domain are not folded. In both ATXN7-SCA7 andATXN7L3-SCA7, the large sequence insertion between the first and second zinc-coordinating cysteines corresponds to a protruding extended hairpin structure.The core of the zinc-binding sites shows a conserved structure formed by twoshort adjacent loops located at the bottom of the hairpin. Although the SCA7domains of both ATXN7 and ATXN7L3 contain two α-helices, these are notlocated at similar positions in the sequences. In ATXN7-SCA7, the two alpha-helices are located downstream from the zinc-binding site and are separated bya loop containing a large number of positively charged residues. In ATXN7L3-SCA7, the two helices lie to either side of the zinc-binding site, leading toa different packing of the two helices. In ATXN7-SCA7, the two helices have analmost perpendicular orientation, the alpha2 helix being anchored to the zinc-binding site. In ATXN7L3-SCA7, the helices alpha1 and alpha2 adopt an anti-parallel orientation defined by hydrophobic interactions. The ATXN7-SCA7domain binds to the core or the C-terminal ends of the histone H2A and H2Bdimer, a region located on the lateral face of the nucleosome that containsthe ubiquitinated Lys 120 of H2B. This property is lost in the ATXN7-SCA7domain [, ].This entry represents the SCA7 domain.
