Fig. 2: HAP40 stabilises the structure of HTT via extensive interactions across all subdomains. | Communications Biology

Fig. 2: HAP40 stabilises the structure of HTT via extensive interactions across all subdomains.

From: Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1

Fig. 2

a Representative cryo-EM 2D class averages of HTT-HAP40. Scale bar (white) is 90 Å. Blue and purple arrowheads denote N- and C-HEAT domains of HTT, respectively. Green and yellow arrowheads denote bridge domain of HTT and HAP40, respectively. b Cryo-EM volume of HTT-HAP40 resolved to 2.6 Å with (i) HTT N-HEAT in blue, bridge domain in green, C-HEAT in purple and HAP40 in yellow or (ii) map shown with HTT-HAP40 modelled in using the same domain colour convention. c Domain organisation of HTT shown mapped to linear sequence. Unresolved regions of the structure are in grey and the three different constructs used in this study are detailed comprising wild-type (23 glutamines; Q23), mutant (54 glutamines; Q54), or HTT with exon 1 partially deleted (Δexon 1; comprising residues 80–3144). d Superposition of our model (PDBID: 6X9O—same domain colour convention as before) and the previous model (PDBID: 6EZ8—all grey) with alignment calculated over N-HEAT and bridge domains. Additional α-helices observed in either of the models are indicated with boxes, C-HEAT domain shift is shown with an arrow. e Surface representation of HTT and HAP40 (same domain colour convention as before) in front and side views, rotated 90°, with additional panel (right) showing same side view of the complex in cartoon format. f Electrostatic surface representation of HTT with HAP40 removed from the structure. Positively charged regions are shown in blue, neutral regions in white and negatively charged regions in red. The positively charged tract in the N-HEAT domain is indicated with a black arrowhead. Hydrophobic HTT surface that binds HAP40 is indicated with hollow black boxes. g Surface representation of HTT-HAP40 complex, coloured according to Consurf conservation scores: from teal for the least conserved residues (1), to maroon for the most conserved residues (9). Conserved surfaces for C-HEAT, bridge and N-HEAT domains are indicated with purple, green and blue arrowheads, respectively. Variable N-HEAT and C-HEAT surfaces are indicated with orange and pink arrowheads, respectively. h HTT (pale blue)-HAP40 (orange) complex in cartoon with pocket predicted to be druggable shown as red volume.

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