Structural basis of diverse membrane target recognitions by ankyrins

Wang, Chao; Wei, Zhiyi; Chen, Keyu; Ye, Fei; Yu, Cong; Bennett, Vann; Zhang, Mingjie

doi:10.7554/elife.04353

Cited by 75 publications

(131 citation statements)

References 72 publications

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“…Structural and biochemical characterization of the scaffolding molecule ank-G has shown that the ANK repeat domain contains several target binding sites (9). In agreement with this finding, Xu and Cooper reported that the modes of Na V and KCNQ2/3 binding to ank-G differ from each other (10).…”

Section: Discussionmentioning

confidence: 68%

“…Localization of KCNQ2/3 channels of the K V 7 family to the AIS has been proposed to follow the model of VGSCs, because KCNQ2/3 channels contain the same ank-G binding motifs that trap VGSCs (8). Moreover, VGSCs and KCNQ2/3 channels both bind to the ankyrin repeats in ank-G, albeit at distinct but overlapping interaction sites (9,10). However, other determinants for AIS localization outside of the ankyrin-binding motif have been described, thus pointing to additional modes of regulation (11)(12)(13).…”

mentioning

confidence: 99%

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FGF14 is a regulator of KCNQ2/3 channels

Pablo

Pitt

2016

Proc. Natl. Acad. Sci. U.S.A.

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KCNQ2/3 (Kv7.2/7.3) channels and voltage-gated sodium channels (VGSCs) are enriched in the axon initial segment (AIS) where they bind to ankyrin-G and coregulate membrane potential in central nervous system neurons. The molecular mechanisms supporting coordinated regulation of KCNQ and VGSCs and the cellular mechanisms governing KCNQ trafficking to the AIS are incompletely understood. Here, we show that fibroblast growth factor 14 (FGF14), previously described as a VGSC regulator, also affects KCNQ function and localization. FGF14 knockdown leads to a reduction of KCNQ2 in the AIS and a reduction in whole-cell KCNQ currents. FGF14 positively regulates KCNQ2/3 channels in a simplified expression system. FGF14 interacts with KCNQ2 at a site distinct from the FGF14-VGSC interaction surface, thus enabling the bridging of Na V 1.6 and KCNQ2. These data implicate FGF14 as an organizer of channel localization in the AIS and provide insight into the coordination of KCNQ and VGSC conductances in the regulation of membrane potential.FGF14 | KCNQ2 | fibroblast growth factor homologous factors | axon initial segment | ankyrin-G N eurons express a wide diversity of ion channels and yet are able to target different channels specifically to cellular subcompartments such as the axon initial segment (AIS) (1, 2). Among the channels specifically targeted to the AIS are the voltage-gated sodium channels (VGSCs) and KCNQ2/3 (Kv7.2/ Kv7.3) voltage-gated potassium channels (3-5). VGSCs are trapped in the AIS through binding to the scaffolding protein ankyrin-G (ank-G), which anchors transmembrane molecules to the spectrin-actin cytoskeleton (4, 6, 7). Localization of KCNQ2/3 channels of the K V 7 family to the AIS has been proposed to follow the model of VGSCs, because KCNQ2/3 channels contain the same ank-G binding motifs that trap VGSCs (8). Moreover, VGSCs and KCNQ2/3 channels both bind to the ankyrin repeats in ank-G, albeit at distinct but overlapping interaction sites (9, 10). However, other determinants for AIS localization outside of the ankyrin-binding motif have been described, thus pointing to additional modes of regulation (11-13).The tight colocalization of K V 7 channels with VGSCs has been postulated to confer specific coregulatory properties. In the soma, dendrites, and AIS, K V 7 channels attenuate subthreshold depolarization by opposing a VGSC persistent current, whereas in the nodes, K V 7 channels stabilize the membrane potential and protect VGSC channels from inactivation (14). Although ank-G serves as an AIS anchor for both K V 7 channels and VGSCs, simultaneous binding of both channels to one ank-G molecule has not been demonstrated, and the molecular mechanisms underlying the coordination between Kv7 channels and VGSCs are incompletely understood. We hypothesized that fibroblast growth factor homologous factors (FHFs), a subfamily (FGF11-14) of fibroblast growth factors that function as intracellular modulators of VGSCs (15,16) channels is not known. Here, we focused on the neuronally restricted FGF14 because...

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Section: Discussionmentioning

confidence: 68%

mentioning

confidence: 99%

FGF14 is a regulator of KCNQ2/3 channels

Pablo

Pitt

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Repeats 5 and 6 are coded on the same exon (exon 6 in vertebrates; Fig. 5E) and are the only repeats that break the canonical 33 residue per repeat pattern (39) and structure (14,40); see "Discussion"). Deletion of exon 6/R5-6 resulted in an N-R4 fragment that showed markedly reduced binding to either anchor (Fig.…”

Section: Ck2 Inhibitor Treatment Decreases Co-localization Of Mb-gfp mentioning

confidence: 99%

“…Each 33-residue ankyrin repeat consists of a right-handed solenoid: half ␤-hairpin, two short antiparallel ␣-helices, a "loop" directed back toward the hairpin, and a second half ␤-hairpin. This pattern is followed in AnkG R1-7, except for R5-R6, which preserves the solenoidal periodicity but replaces the hairpin with a longer R6 front helix and longer loop (40). Locations of hairpin tips residues H1, H2, H4, H5, and H7 are labeled green; H3 tip KK implicated in Na v binding is labeled red.…”

Section: A Ankg Mb Domainmentioning

confidence: 99%

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An Ankyrin-G N-terminal Gate and Protein Kinase CK2 Dually Regulate Binding of Voltage-gated Sodium and KCNQ2/3 Potassium Channels

Cooper

2015

Journal of Biological Chemistry

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Background: Neuronal axons use dense clusters of voltage-gated ion channels to conduct rapid electrical signals called action potentials. Results:We mapped sites on a cytoskeletal protein, ankyrin-G, which binds and clusters sodium and potassium channels. Conclusion: Channel binding is dually regulated by protein kinase CK2 phosphorylation and the ankyrin-G sequence. Significance: The new mechanisms identified control axonal membrane excitability and are drug development candidates.

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How the TRPA1 receptor transmits painful stimuli: Inner workings revealed by electron cryomicroscopy

Brewster

Gaudet

2015

BioEssays

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Summary A new high-resolution structure of a pain-sensing ion channel, TRPA1, provides a molecular scaffold to understand channel function. Unexpected structural features include a TRP-domain helix similar to TRPV1, a novel ligand-binding site, and an unusual C-terminal coiled coil stabilized by inositol hexakisphosphate (IP6). TRP-domain helices, which structurally act as a nexus for communication between the channel gates and its other domains, may thus be a feature conserved across the entire TRP family and, possibly, other allosterically-gated channels. Similarly, the TRPA1 antagonist-binding site could also represent a druggable location in other ion channels. Combined with known TRPA1 functional properties, the structural role for IP6 leads us to propose that polyphosphate unbinding could act as a molecular kill switch for TRPA1 inactivation. Finally, although packing of the TRPA1 membrane-proximal region hints at a mechanism for electrophile sensing, the details of how TRPA1 responds to noxious reactive electrophiles and temperature await future studies.

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Structural basis of diverse membrane target recognitions by ankyrins

Cited by 75 publications

References 72 publications

FGF14 is a regulator of KCNQ2/3 channels

FGF14 is a regulator of KCNQ2/3 channels

An Ankyrin-G N-terminal Gate and Protein Kinase CK2 Dually Regulate Binding of Voltage-gated Sodium and KCNQ2/3 Potassium Channels

How the TRPA1 receptor transmits painful stimuli: Inner workings revealed by electron cryomicroscopy

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