IndraLab

Statements

CALM binds KCNQ5. 49 / 49
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"The PIP 2 -bound structure KCNQ5–CaM PIP2 displayed several features that are different from previously reported PIP 2 -bound KCNQ structures."
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"To reveal the PIP 2 activation mechanism of KCNQ5, we aligned closed-conformation KCNQ5–CaM PIP2-HN37-C and open-conformation KCNQ5–CaM PIP2-HN37-O in the whole channel context ( xref )."
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"Therefore, KCNQ5–CaM apo is in a decoupled conformation, with activated VSDs and a closed PD (gate)."
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"In KCNQ5–CaM PIP2-HN37-C , the PIP 2 in the P3 site mainly interacts with positively charged residues in the C-terminal segment of S6 and does not induce any major conformational change of S6 ( xref and)."
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"The overall structure of KCNQ5–CaM apo is similar to structures of the apo KCNQ2 and KCNQ4, which are also in a decoupled conformation with activated VSDs and a closed PD () ( xref xref – xref )."
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"In KCNQ5–CaM PIP2-HN37-O , we initially observed one PIP 2 molecule bound in the P2 site, similar to that in KCNQ2-CaM CBD-PIP2 and KCNQ2-CaM PIP2-HN37 in the open conformation ( xref and) ( xref )."
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"Thus, this KCNQ5–CaM PIP2 structure likely presents a state where PIP 2 binds but does not activate the channel ( xref )."
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"By contrast, in KCNQ5–CaM PIP2-HN37-O , due to the polar interactions between the two PIP 2 molecules and the S6 C-terminal segment, PIP 2 induces the bending of the S6 C-terminal segment at the conserved PAG segment away from the central axis of the channel pore ( xref and xref )."
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"The structural and computational analyses of KCNQ5–CaM PIP2-HN37-C and KCNQ5–CaM PIP2-HN37-O suggest a binding-opening model, where PIP 2 binding in the P2 site accompanies the channel opening ( xref )."
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"In KCNQ5–CaM PIP2 , the P3 site is located in the hydrophobic groove between two adjacent VSDs, and PIP 2 bound in this site interacts with neither VSD ( xref )."
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"Here, we report cryoelectron microscopy structures of the human KCNQ5–calmodulin (CaM) complex in the apo, PIP 2 -bound, and both PIP 2 - and the activator HN37-bound states in either a closed or an open conformation."
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"PIP 2 Binds in S6 of KCNQ5–CaM PIP2 in a Closed Conformation."
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"In the structure of KCNQ5–CaM PIP2 , the PIP 2 binds in the middle of the hydrophobic groove between two adjacent VSDs, whereas in the same site of KCNQ5–CaM apo , no similar density was observed ( xref and)."
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"First, this KCNQ5–CaM PIP2 structure is a high-resolution KCNQ structure with only PIP 2 but no other ligand or auxiliary subunit bound."
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"The distribution pattern of the voltage-dependent potassium channel KCNQ5 in the rat retina and the changes that took place during photoreceptors loss, which are shown in this study, support the hypot[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Notably, by interacting with Lys361 in S6, PIP 2 stabilizes the channel in the open conformation, as shown by the 8 to 9 Å shortest diagonal atom-to-atom distance at the activation gate in KCNQ5–CaM PIP2-HN37-O ( xref )."
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"We herein demonstrate that CaM also interacts with KCNQ5 in the rat retina and that this interaction can act as a marker during the retinal degeneration process."
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"PIP 2 - and HN37-Bound KCNQ5–CaM Adopts Both Closed and Open Conformations."
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"Based not only on these observations, but also on arguments in other studies ( Gamper et al., 2005; Yus-Najera et al., 2002 ), we propose a correlation between the retinal degeneration progress and th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In this study, using the KCNQ5 as a model, we captured structures of one apo closed KCNQ5 (KCNQ5–CaM apo ), two PIP 2 -bound closed KCNQ5 (KCNQ5–CaM PIP2 and KCNQ5–CaM PIP2-HN37-C ), and one PIP 2 -bound open KCNQ5 (KCNQ5–CaM PIP2-HN37-O )."
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"Thus, the two PIP 2 molecules in the P2 and P3 sites in KCNQ5–CaM PIP2-HN37-O work synergistically to stabilize the channel in the open conformation from two sides of the same S6 C-terminal segment ( xref )."
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"Third, the KCNQ5–CaM PIP2 revealed a different PIP 2 -binding site in the KCNQ family, which we name the P3 site to distinguish it from previously observed two PIP 2 -binding sites (P1 and P2) ( xref ) ( xref )."
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"Without HN37, the PIP 2 alone was not able to stabilize KCNQ5 in the open conformation, as shown by the structure of KCNQ5–CaM PIP2 ( xref )."
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"Moreover, KCNQ5–CaM PIP2-HN37-C and KCNQ5–CaM PIP2 are virtually in the same closed conformation ()."
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"In comparison, the PIP 2 -binding modes in KCNQ5–CaM PIP2-HN37-C and KCNQ5–CaM PIP2-HN37-O structures are different."
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"Structure Determination of KCNQ5–CaM in Complex with PIP 2 and HN37."
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"To further verify these two PIP 2 -binding sites, we ran coarse-grained molecular dynamic (MD) simulations using the structures of KCNQ5–CaM PIP2-HN37-C and KCNQ5–CaM PIP2-HN37-O as models."
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"In KCNQ5–CaM PIP2 , the activation gate remains closed, as shown by the 4 to 6 Å atom-to-atom distance between diagonal constriction-lining residues ( xref )."
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"Moreover, different from the PIP 2 in KCNQ5–CaM PIP2 that interacts with residues His358, Lys361, and His362 in the C-terminal segment of S6, in KCNQ5–CaM PIP2-HN37-O , after structural rearrangement, the PIP 2 in the P3 site interacts with Lys353 in S6 of the adjacent subunit from the other side ( xref )."
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"In this study, using the activator HN37 in combination with PIP 2 , we were able to capture the open-conformation structure of KCNQ5 (KCNQ5–CaM PIP2-HN37-O )."
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"Moreover, the KCNQ5–CaM PIP2 adopts a very similar conformation as KCNQ5–CaM apo , with no structural rearrangement occurring in the CTD and CaM ( xref )."
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"In this study, we present structures of the human KCNQ5–CaM complex in the apo closed, PIP 2 -bound closed, and PIP 2 - and HN37-bound closed and open conformations and decipher the PIP 2 activation of neuronal KCNQ channels."
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"In KCNQ5–CaM PIP2-HN37-C , PIP 2 binds in the P3 site ( xref ), like that in KCNQ5–CaM PIP2 ( xref )."
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"To reveal activation mechanisms of KCNQ5 by PIP 2 , we determined four cryoelectron microscopy (cryo-EM) structures of the KCNQ5–CaM complex using the KCNQ5Δ-CaM protein sample in the absence and presence of PIP 2 and HN37 ( xref and): the apo KCNQ5–CaM structure (KCNQ5–CaM apo ) in a closed conformation at 2.4 Å resolution ( xref and), the PIP 2 -bound KCNQ5–CaM structure (KCNQ5–CaM PIP2 ) in a closed conformation at 3.1 Å resolution ( xref and), and two PIP 2 - and HN37-bound KCNQ5–CaM structures with one in a closed conformation (KCNQ5–CaM PIP2-HN37-C ) at 3.2 Å resolution and the other in an open conformation (KCNQ5–CaM PIP2-HN37-O ) at 2.9 Å resolution ( xref and)."
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"Intracellular Ca 2+ recordings of glial cells were carried out in the NFL of the retinas at P100 when the KCNQ5/CaM interaction was at its greatest."
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"Although the KCNQ5/CaM interaction increased as a result of age in the SD retinas, it was significantly higher in the P23H-1 rats during retinal degeneration."
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"In comparison, HN37 binds in a conserved pocket in the TMD of KCNQ5–CaM PIP2-HN37-C and KCNQ5–CaM PIP2-HN37-O ( xref ), with clearly resolved density in the EM map ( xref and)."
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"KCNQ5–CaM apo Has Activated VSDs and a Closed Pore."
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"Based not only on these observations, but also on arguments in other studies ( Gamper et al., 2005; Yus-Najera et al., 2002 ), we propose a correlation between the retinal degeneration progress and th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The PIP 2 Activation Mechanism of KCNQ5–CaM."
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"If the effect of the KCNQ5/CaM interaction on the retina was similar to that in CHO cells and yeast, we can assume that the open probability of the potassium channels in the inner retina lowered and, [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In the three ligand-bound structures, namely KCNQ5–CaM PIP2 , KCNQ5–CaM PIP2-HN37-C , and KCNQ5–CaM PIP2-HN37-O , the density for the inositol 1,4,5-trisphosphate head group of PIP 2 was better resolved in the EM map, whereas the density for the flexible fatty acid chains of PIP 2 was poorly resolved, likely due to their dynamic interactions with the TMD of the channel ( xref and)."
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"The open conformation structure of KCNQ5–CaM PIP2-HN37-O here provides more structural evidence to support the potency of HN37 for the activation of multiple neuronal KCNQ channels ( xref )."
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"Meanwhile, the CTD and CaM in KCNQ5–CaM PIP2-HN37-O undergo large structural rearrangements, with an ~180° rotation of HA/HB/CaM and a transform of S6/loop/HA to one continuous helix ( xref ), similar to those observed in KCNQ1, KCNQ2, and KCNQ4 in the open conformation ( xref , xref , xref ) ()."
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"Second, this KCNQ5–CaM PIP2 structure is a PIP 2 -bound KCNQ structure in a closed conformation ( xref )."
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"In addition, careful examination of the P3 site in the map of KCNQ5–CaM PIP2-HN37-O suggested a second PIP 2 molecule, which features a large, planar density for the inositol 1,4,5-trisphosphate head group ( xref and)."
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"To pursue an open conformation of KCNQ5, we further determined two structures of both PIP 2 - and HN37-bound KCNQ5 from one dataset (KCNQ5–CaM PIP2-HN37-C and KCNQ5–CaM PIP2-HN37-O ) ( xref and xref and)."
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"Compared with that in the P3 site in KCNQ5–CaM PIP2-HN37-C , the head group of PIP 2 in the P3 site in KCNQ5–CaM PIP2-HN37-O shifts upward and outward by ~4.1 Å ( xref )."
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"In the TMD of the KCNQ5–CaM apo structure, four KCNQ5 subunits assemble into a tetrameric ion channel in a domain-swapped arrangement, with the VSD (S1–S4) from one subunit interacting with the PD (S5–S6) from the adjacent subunit ( xref )."
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