PIP2 and PIP3 interact with N-terminus region of TRPM4 channel

Boušová, Kristýna; Jirku, Michaela; Bumba, Ladislav; Bednářová, Lucie; Šulc, Miroslav; Franěk, Miloslav; Vyklicky, Ladislav; Vondrášek, Jiřı́; Teisinger, Jan

doi:10.1016/j.bpc.2015.06.004

Cited by 26 publications

(18 citation statements)

References 72 publications

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“…Some channels, including TRPV5, TRPV6, TRPM4, TRPM5, and TRPM8, are positively modulated ( Rohacs, 2014 ); others, such as TRPC4 andTRPP2 ( Otsuguro et al, 2008 ; Ma et al, 2005 ), are negatively regulated, whereas TRPV1 channel function is stimulated or inhibited by PIP2, depending on the experimental conditions ( Rohacs et al, 2008 ; Lukacs et al, 2007 ). Although PIP2 is known to bind to cationic residues in some TRPs in vitro, including TRPV1, TRPM8, and TRPM4 ( Rohacs et al, 2005 ; Bousova et al, 2015 ; Poblete et al, 2015 ), it remains largely unclear as to the structural basis of the PIP2 regulation.…”

Section: Introductionmentioning

confidence: 99%

Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2

et al. 2018

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Transient receptor potential (TRP) channels are regulated by diverse stimuli comprising thermal, chemical, and mechanical modalities. They are also commonly regulated by phosphatidylinositol-4,5-bisphosphate (PIP2), with underlying mechanisms largely unknown. We here revealed an intramolecular interaction of the TRPP3 N and C termini (N-C) that is functionally essential. The interaction was mediated by aromatic Trp81 in pre-S1 domain and cationic Lys568 in TRP-like domain. Structure-function analyses revealed similar N-C interaction in TRPP2 as well as TRPM8/-V1/-C4 via highly conserved tryptophan and lysine/arginine residues. PIP2 bound to cationic residues in TRPP3, including K568, thereby disrupting the N-C interaction and negatively regulating TRPP3. PIP2 had similar negative effects on TRPP2. Interestingly, we found that PIP2 facilitates the N-C interaction in TRPM8/-V1, resulting in channel potentiation. The intramolecular N-C interaction might represent a shared mechanism underlying the gating and PIP2 regulation of TRP channels.

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Section: Introductionmentioning

confidence: 99%

Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2

et al. 2018

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“…Like all TRPs, each monomer contains six transmembrane-spanning segments, and a selectivity filter for ions is located in the loop connecting the fifth and sixth transmembrane domains [15][16][17]. The cytoplasmic N-and C termini contain numerous binding regions for calmodulin (CaM), cytosolic ATP, phosphatidylinositol 4, 5-bisphosphate (PIP2) and putative phosphorylation sites for protein kinase A (PKA) and protein kinase C (PKC) [18][19][20][21]. TRPM4 is capable of transporting monovalent cations [22].…”

Section: Introductionmentioning

confidence: 99%

Shared CaM‐ and S100A1‐binding epitopes in the distal TRPM4 N terminus

et al. 2017

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The transient receptor potential channel of melastatin 4 (TRPM4) belongs to a group of large ion receptors that are involved in countless cell signalling cascades. This unique member is ubiquitously expressed in many human tissues, especially in cardiomyocytes, where it plays an important role in cardiovascular processes. Transient receptor potential channels (TRPs) are usually constituted by intracellular N- and C- termini, which serve as mediators affecting allosteric modulation of channels, resulting in the regulation of the channel function. The TRPs tails contain a number of conserved epitopes that specifically bind the intracellular modulators. Here, we identify new binding sites for the calmodulin (CaM) and S100 calcium-binding protein A1 (S100A1), located in the very distal part of the TRPM4 N terminus. We have used chemically synthesized peptides of the TRPM4, mimicking the binding epitopes, along with fluorescence methods to determine and specify CaM- and S100A1-binding sites. We have found that the ligands binding epitopes at the TRPM4 N terminus overlap, but the interacting mechanism of both complexes is probably different. The molecular models supported by data from the fluorescence method confirmed that the complexes formations are mediated by the positively charged (R139, R140, R144) and hydrophobic (L134, L138, V143) residues present at the TRPM4 N terminus-binding epitopes. The data suggest that the molecular complexes of TRPM4/CaM and TRPM4/S100A1 would lead to the modulation of the channel functions.

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“…The pre-S1 shoulder helix contains large hydrophobic residues buried in the membrane and a number of charged residues facing the cytosol. Among these charged residues, Arg767 was identified as important for interactions with the phosphatidylinositol lipids, PIP2 and PIP3 (25). …”

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confidence: 99%

Structure of the human TRPM4 ion channel in a lipid nanodisc

Autzen

Myasnikov

Campbell

et al. 2018

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Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage dependent manner, but unlike many other TRP channels is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3Å resolution as determined by single particle electron cryo-microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium binding site within the intracellular side of the S1–S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening.

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PIP2 and PIP3 interact with N-terminus region of TRPM4 channel

Cited by 26 publications

References 72 publications

Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2

Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2

Shared CaM‐ and S100A1‐binding epitopes in the distal TRPM4 N terminus

Structure of the human TRPM4 ion channel in a lipid nanodisc

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