Structural insight into TRPV5 channel function and modulation

Dang, Shangyu; Goor, M.K. van; Asarnow, Daniel; Wang, Yongqiang; Julius, David; Cheng, Yifan; Wijst, Jenny van der

doi:10.1073/pnas.1820323116

Cited by 86 publications

(57 citation statements)

References 49 publications

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“…The binding role of CaM amino acids at the position around 130 has been confirmed in the TRPV6/CaM and TRPV5/CaM structures, and the amino acids have been identified as critical positions for the interactions. In the presented molecular model, we have confirmed the same CaM amino acids involved in interactions with TRPM6np (specifically: E120 and M144) [36]. The interpretation of the TRPM6np/CaM and TRPM6np/S100A1 models is strongly supported by data from fluorescence anisotropy experiments, indicating the synergy of the basic residues in individual clusters.…”

Section: Discussionsupporting

confidence: 64%

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TRPM6 N-Terminal CaM- and S100A1-Binding Domains

Zouharová

Heřman

Hofbauerová

et al. 2019

IJMS

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Transient receptor potential (TRPs) channels are crucial downstream targets of calcium signalling cascades. They can be modulated either by calcium itself and/or by calcium-binding proteins (CBPs). Intracellular messengers usually interact with binding domains present at the most variable TRP regions—N- and C-cytoplasmic termini. Calmodulin (CaM) is a calcium-dependent cytosolic protein serving as a modulator of most transmembrane receptors. Although CaM-binding domains are widespread within intracellular parts of TRPs, no such binding domain has been characterised at the TRP melastatin member—the transient receptor potential melastatin 6 (TRPM6) channel. Another CBP, the S100 calcium-binding protein A1 (S100A1), is also known for its modulatory activities towards receptors. S100A1 commonly shares a CaM-binding domain. Here, we present the first identified CaM and S100A1 binding sites at the N-terminal of TRPM6. We have confirmed the L520-R535 N-terminal TRPM6 domain as a shared binding site for CaM and S100A1 using biophysical and molecular modelling methods. A specific domain of basic amino acid residues (R526/R531/K532/R535) present at this TRPM6 domain has been identified as crucial to maintain non-covalent interactions with the ligands. Our data unambiguously confirm that CaM and S100A1 share the same binding domain at the TRPM6 N-terminus although the ligand-binding mechanism is different.

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Section: Discussionsupporting

confidence: 64%

“…The hydrolysis of PIP2 by phospholipase C in the presence of other agonists can lead to TRPM6 gating. Otherwise, TRPM6 activity is suppressed by free intracellular Mg 2+ [14,34,35]; channel regulation by Ca 2+ has not been proved [34,35,36].…”

Section: Introductionmentioning

confidence: 99%

TRPM6 N-Terminal CaM- and S100A1-Binding Domains

Zouharová

Heřman

Hofbauerová

et al. 2019

IJMS

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“…Some TRP channels undergo Ca 2+ -dependent inactivation and, in TRPV5 and TRPV6, this process is mediated through direct interaction with calmodulin (CaM; Nilius et al, 2003; Lambers et al, 2004). The recently reported structures of TRPV5 or TRPV6 bound with CaM showed that a lysine residue, located at the H6–H7 loop of CaM, inserts its side chain into the cytoplasmic entryway of channel pore, where it establishes cation-π interactions with a ring of four tryptophan residues (one from each subunit), leading to inward movement of the lower half of S6 helices, and consequently, pore closure (Hughes et al, 2018b; Singh et al, 2018b; Dang et al, 2019).…”

Section: The “Resolution Revolution” Led To Breakthrough In Trpv1 Structural Biologymentioning

confidence: 99%

Structural mechanisms of transient receptor potential ion channels

Cao

2020

Journal of General Physiology

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Transient receptor potential (TRP) ion channels are evolutionarily ancient sensory proteins that detect and integrate a wide range of physical and chemical stimuli. TRP channels are fundamental for numerous biological processes and are therefore associated with a multitude of inherited and acquired human disorders. In contrast to many other major ion channel families, high-resolution structures of TRP channels were not available before 2013. Remarkably, however, the subsequent “resolution revolution” in cryo-EM has led to an explosion of TRP structures in the last few years. These structures have confirmed that TRP channels assemble as tetramers and resemble voltage-gated ion channels in their overall architecture. But beyond the relatively conserved transmembrane core embedded within the lipid bilayer, each TRP subtype appears to be endowed with a unique set of soluble domains that may confer diverse regulatory mechanisms. Importantly, TRP channel structures have revealed sites and mechanisms of action of numerous synthetic and natural compounds, as well as those for endogenous ligands such as lipids, Ca2+, and calmodulin. Here, I discuss these recent findings with a particular focus on the conserved transmembrane region and how these structures may help to rationally target this important class of ion channels for the treatment of numerous human conditions.

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“…Soon after cloning Eag1 channels, it was found that removal of PAS-Cap caused modifications in gating that were compensated by a mutation in the S4/5 linker, leading to the proposal that it may functionally interact with PAS-Cap. It was also found that the ∆7-12 deletion (RRGLVA) of PAS-Cap resulted in rapid inactivation [33]. Because the voltage-dependency was altered, the authors speculated that the N-terminus may work together with regions close to S4 within the voltage sensor.…”

Section: Interplay Between Pas-cap and The S4/5 Linker In Eag Channelsmentioning

confidence: 99%

“…Thus, the VSD is uncoupled from the PD in both cases, but the role of CaM for this disengagement, if any, is unclear. The functional compensation of ∆7-12 by a S4/5 mutation, the proximity of the PAS-Cap in the open conformation of hERG [33], and the impact of ∆3-9 and R7A/R8A mutant on function, suggest that R7/R8 might form a functional interaction with D342 in S4/5 [20]. Mutation-function studies suggest that PAS-Cap can be divided into two segments, the unstructured N-terminus (residues 1-9, not seen in the cryo-EM structures) and the unstructured C-terminal (residues 10-13) that precedes the amphipathic alpha helix (residues [16][17][18][19][20][21][22][23][24][25].…”

Section: Interplay Between Pas-cap and The S4/5 Linker In Eag Channelsmentioning

confidence: 99%

Atomistic Insights of Calmodulin Gating of Complete Ion Channels

Nuñez

Muguruza-Montero

Villarroel

2020

IJMS

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Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca2+ signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K+, and direct permeation of this cation through specialized channels. Calmodulin (CaM), through direct binding to these proteins, participates in setting the membrane potential and the overall permeability to Ca2+. Over the past years many structures of complete channels in complex with CaM at near atomic resolution have been resolved. In combination with mutagenesis-function, structural information of individual domains and functional studies, different mechanisms employed by CaM to control channel gating are starting to be understood at atomic detail. Here, new insights regarding four types of tetrameric channels with six transmembrane (6TM) architecture, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1–5, and its regulation by CaM are described structurally. Different CaM regions, N-lobe, C-lobe and EF3/EF4-linker play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its target that are only evidenced in the full-channel structure. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effect through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar alpha-helices, they do so using different docking strategies. We discuss how this allows selective action of drugs with great therapeutic potential.

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Structural insight into TRPV5 channel function and modulation

Cited by 86 publications

References 49 publications

TRPM6 N-Terminal CaM- and S100A1-Binding Domains

TRPM6 N-Terminal CaM- and S100A1-Binding Domains

Structural mechanisms of transient receptor potential ion channels

Atomistic Insights of Calmodulin Gating of Complete Ion Channels

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