The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs

Shen, Peter; Yang, Xiaoyong; DeCaen, Paul G.; Liu, Xiaowen; Bulkley, David; Clapham, David E.; Cao, Erhu

doi:10.1016/j.cell.2016.09.048

Cited by 222 publications

(379 citation statements)

References 76 publications

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“…The residues of FIYMV on S6 just below the selectivity filter region form a π-helix (Fig. 3a), a structural feature that was also observed in other TRP channel structures 23,25 and may facilitate the bending of S6 inner helix for channel gating.…”

Section: Main Textmentioning

confidence: 57%

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Structure of mammalian endolysosomal TRPML1 channel in nanodiscs

Chen

She

Zeng

et al. 2017

Nature

255

170

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Transient receptor potential mucolipin 1 (TRPML1) is an endo/lysosomal cation channel ubiquitously expressed in mammalian cells1,2 and its loss-of-function mutations are the direct cause of Type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease3-6. Here we present the single particle cryo-electron microscopy (cryo-EM) structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis, the TRPML1 structure reveals that phosphatidylinositol bisphosphate (PIP2) binds to the N-terminus of the channel – distal from the pore – and the helix-turn-helix extension between S2 and S3 likely couples ligand binding to pore opening. The tightly packed selectivity filter contains multiple ion binding sites and the conserved acidic residues form the luminal Ca2+ blocking site that confers luminal pH and Ca2+ modulation on channel conductance. A luminal linker domain forms a fenestrated canopy atop the channel, providing multiple luminal ion passages to the pore and also creating a negative electrostatic trap – preferably for divalent cations at the luminal entrance. The structure also reveals two equally distributed S4-S5 linker conformations in the closed channel, providing structural implication for the S4-S5 linker-mediated PIP2 gating mechanism among TRPML channels7,8.

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Section: Main Textmentioning

confidence: 57%

“…1b and Fig. 3e), a characteristic feature of group 2 TRP channels including TRPML and TRPP 25,26 (Extended Data Fig. 8).…”

Section: Main Textmentioning

confidence: 97%

Structure of mammalian endolysosomal TRPML1 channel in nanodiscs

Chen

She

Zeng

et al. 2017

Nature

255

170

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“… a–i , Pairwise superposition of the pore domain in hTRPV6 with ( a ) rat TRPV1 18 (PDB ID: 5IRX; RMSD = 2.065 Å), ( b ) rabbit TRPV2 21 (PDB ID: 5AN8; RMSD = 3.757 Å), ( c ) rat TRPV2 24 (PDB ID: 5HI9; RMSD = 4.399 Å), ( d ) human TRPA1 23 (PDB ID: 3J9P; RMSD = 1.429 Å), ( e ) human PKD2 25 (PDB ID: 5T4D; RMSD = 2.676 Å), ( f ) KcsA from Streptomyces lividans 47 (PDB ID: 1BL8; RMSD = 2.708 Å), ( g ) MthK from M. thermautotrophicum 48 (PDB ID: 1LNQ; RMSD = 2.947 Å), ( h ) rat Shaker 49 (PDB ID: 2A79; RMSD = 2.487 Å) and ( i ) rat GluA2 AMPA-subtype iGluR 28 (PDB ID: 5WEO; RMSD = 2.044 Å). j , Sequence alignment for the pore region of human TRPV3–6, TRPA1 and PKD2, rat TRPV1, 2, 6, Shaker and GluA2, rabbit TRPV2 and bacterial K + channels KcsA and MthK.…”

Section: Extended Datamentioning

confidence: 99%

“…5, Supplementary Video 1). Despite other representatives of the TRP channel family have a local α-to-π helical transition in the middle of S6 18,23–25 , they lack the alanine gating hinge (Extended Data Fig. 9).…”

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confidence: 99%

Opening of the human epithelial calcium channel TRPV6

McGoldrick

Singh

Saotome

et al. 2017

Nature

190

322

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Ca2+-selective transient receptor potential vanilloid subfamily member 6 (TRPV6) channels play a critical role in calcium uptake in epithelial tissues1–4. Altered TRPV6 expression is associated with a variety of human diseases5, including cancers6. TRPV6 channels are constitutively active1,7,8 and their open probability depends on the lipidic composition of the membrane, increasing significantly in the presence of phosphatidylinositol 4,5-bisphosphate (PIP2)7,9. We previously solved crystal structures of detergent-solubilized rat TRPV6 in the closed state10,11. Corroborating previous electrophysiological studies3, these structures demonstrated that the Ca2+ selectivity of TRPV6 arises from a ring of aspartate side chains in the selectivity filter that tightly binds Ca2+. However, it has remained unknown how TRPV6 channels open and close their pores for ion permeation. Here we present cryo-EM structures of human TRPV6 in the open and closed states. The channel selectivity filter adopts similar conformations in both states, consistent with its explicit role in ion permeation. The iris-like channel opening is accompanied by an α-to-π helical transition in the pore-lining S6 helices at an alanine hinge just below the selectivity filter. As a result of this transition, the S6 helices bend and rotate, exposing different residues to the ion channel pore in the open and closed states. This novel gating mechanism, which defines the constitutive activity of TRPV6, is unique for tetrameric ion channels and provides new structural insights for understanding their diverse roles in physiology and disease.

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“…Despite their large size and potential functional importance, very little was known about these extracellular loops until recently. During the preparation of this paper, three TRPP2 cryo-electron microscopy (cryo-EM) structures were reported (9,10,14). From these structures, it can be seen that the TRPP2 extracellular loops are involved in the homomeric assembly of the TRPP2 channel and may also be important for ion permeability and channel function regulation (9,10).…”

mentioning

confidence: 99%

Extracellular Loops Are Essential for the Assembly and Function of Polycystin Receptor-Ion Channel Complexes

Salehi-Najafabadi¹,

Li²,

Valentino

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellPolycystin complexes, or TRPP-PKD complexes, made of transient receptor potential channel polycystin (TRPP) and polycystic kidney disease (PKD) proteins, play key roles in coupling extracellular stimuli with intracellular Ca 2؉ signals. For example, the TRPP2-PKD1 complex has a crucial function in renal physiology, with mutations in either protein causing autosomal dominant polycystic kidney disease. In contrast, the TRPP3-PKD1L3 complex responds to low pH and was proposed to be a sour taste receptor candidate. It has been shown previously that the protein partners interact via association of the C-terminal or transmembrane segments, with consequences for the assembly, surface expression, and function of the polycystin complexes. However, the roles of extracellular components, especially the loops that connect the transmembrane segments, in the assembly and function of the polycystin complex are largely unknown. Here, with an immunoprecipitation method, we found that extracellular loops between the first and second transmembrane segments of TRPP2 and TRPP3 associate with the extracellular loops between the sixth and seventh transmembrane segments of PKD1 and PKD1L3, respectively. Immunofluorescence and electrophysiology data further confirm that the associations between these loops are essential for the trafficking and function of the complexes. Interestingly, most of the extracellular loops are also found to be involved in homomeric assembly. Furthermore, autosomal dominant polycystic kidney disease-associated TRPP2 mutant T448K significantly weakened TRPP2 homomeric assembly but had no obvious effect on TRPP2-PKD1 heteromeric assembly. Our results demonstrate a crucial role of these functionally underexplored extracellular loops in the assembly and function of the polycystin complexes.

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The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs

Cited by 222 publications

References 76 publications

Structure of mammalian endolysosomal TRPML1 channel in nanodiscs

Structure of mammalian endolysosomal TRPML1 channel in nanodiscs

Opening of the human epithelial calcium channel TRPV6

Extracellular Loops Are Essential for the Assembly and Function of Polycystin Receptor-Ion Channel Complexes

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