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Fig. 1 | Cell Communication and Signaling

Fig. 1

From: Connecting the αα-hubs: same fold, disordered ligands, new functions

Fig. 1

Connecting the αα-hubs. a Hub proteins are involved in diverse functions such as transcription, post-translational modification and organization of cell structure. Hub proteins are shown in the center of protein–protein interaction networks where they organize relevant molecular components. The drawings are based on αα-hub protein functions such as transcriptional regulation (Sin3a) and cell structure organization (harmonin). b Domain structure of αα-hub proteins. Representative parent protein (not drawn to scale) for each of the founding αα-hubs PAH, RST, TAFH and NCBD, as well as the new member HHD. Experimentally-based interactome sizes obtained from the STRING database are shown for each αα-hub. Hp: small hairpin extension of the HHD-PDZ supramodule. c Superimposition of the αα-hairpin super-secondary structure motif. Representatives of each domain type of the αα-hubs (pdb codes 2CZY (PAH1), 2LD7 (PAH3), 5ECJ (TAFH), 2L14 (NCBD), 2KBQ (HHD), 5N9Q (RST)). The zoom illustrates the αL4 link motif found in the prototypical αα-hubs [1], where the highlighted hydrophobic β3-anchor residue forms stabilizing interactions between the two hairpin helices. d Cartoon structures comparing αα-hubs. The PAH1 domain of Sin3a (purple) is compared to the HHDs of CCM2 (red), whirlin (dark orange) and harmonin (bright orange). Top row illustrates the two domains in their free form whereas the second row shows overlays of free PAH1 with whirlin HHD (left) and CCM2 HHD (right) (pdb codes 2RMR (PAH1), 6FDD (whirlin-HHD), 4FQN (CCM2-HHD)). The third row illustrates complexes of the two domains: PAH1 in complex with SAP25 and CCM2 HHD in complex with MEKK3 (pdb codes 2RMS and 4Y5O, respectively). The ligands are shown in grey. The bottom panel displays the harmonin PDZ-HHD supramodule (PDZ in blue) in complex with sans (grey). The short hairpin extension responsible for tethering the PDZ and HHD is shown in light blue. e Disorder profiles of HHD binding ligands cadherin-23 intracellular domain (ICD) and MEKK3. The disorder propensity ranging from 0 to 1 was predicted using IUPred2A (black) [32] and PONDR VSL2 (blue) [33], whereas MoRFs were predicted by MoRFpred (red) [34]. The regions responsible for binding to HHD based on available structures (pdb codes 4Y5O, 2LSR and 2KBR) are highlighted with orange background, whereas the regions binding as α-helix in the hydrophobic cleft are highlighted with white boxes

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