Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2)

Grieben, M.; Pike, A.C.W.; Shintre, C.A.; Venturi, Elisa; El-Ajouz, Sam; Tessitore, A.; Shrestha, L.; Mukhopadhyay, Shubhashish M.M.; Mahajan, P.; Chalk, R.; Burgess-Brown, N.; Sitsapesan, Rebecca; Huiskonen, Juha T.; Carpenter, E.P.

doi:10.1038/nsmb.3343

Cited by 168 publications

(202 citation statements)

References 74 publications

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“…3, lanes 2-4 and 6 -8). The co-IP results of the TRPP loops indicate that, besides the interaction with PKD partners, the S1-S2 loops of these proteins are also involved in homomeric assembly, consistent with the homotetramer formed by this loop in the TRPP2 cryo-EM structures (9,10,14). The homomeric assembly of PKD1L3 is not expected because there is only one copy of PKD1L3 in its complex with TRPP3 (25).…”

Section: Dna Constructs and Cell Surface Expression Of The Trpp And Pmentioning

confidence: 71%

“…In the first round of experimentation, three TRPP2 mutants (R325P, C331S, and R420G) and three PKD1 mutants (L3731Q, L3749P, and Y3819C) were tested. The three TRPP2 amino acids have been shown to be important for stabilizing the TRPP2 S1-S2 loop structure (9,10,14). The three PKD1 amino acids are also predicted to be crucial for protein structure, as seen in a structural model generated based on the TRPP2 cryo-EM structure (Fig.…”

Section: Dna Constructs and Cell Surface Expression Of The Trpp And Pmentioning

confidence: 99%

“…5A). The recently reported TRPP2 homotetrameric structures also indicated that many of these mutated amino acids are potentially important for stabilizing the structure of the S1-S2 loop or the intersubunit interaction between TRPP2 subunits (9,10,14). Therefore, we tested the effects of some mutations on the heteromeric assembly between the TRPP2 and PKD1 loops and the homomeric assembly between TRPP2 loops (Fig.…”

Section: Dna Constructs and Cell Surface Expression Of The Trpp And Pmentioning

confidence: 99%

“…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%

“…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). In this study, we hypothesized that TRPP and PKD proteins also associate through extracellular loops and tested this hypothesis with biochemical and biophysical methods, using the TRPP2-PKD1 and TRPP3-PKD1L3 complexes as model molecules.…”

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confidence: 99%

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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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Section: Dna Constructs and Cell Surface Expression Of The Trpp And Pmentioning

confidence: 71%

Section: Dna Constructs and Cell Surface Expression Of The Trpp And Pmentioning

confidence: 99%

Section: Dna Constructs and Cell Surface Expression Of The Trpp And Pmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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The asparagine 533 residue in the outer pore loop region of the mouse PKD2L1 channel is essential for its voltage‐dependent inactivation

et al. 2017

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Voltage‐dependent inactivation of ion channels contributes to the regulation of the membrane potential of excitable cells. Mouse polycystic kidney disease 2‐like 1 ( PKD 2L1) forms voltage‐dependent nonselective cation channels, which are activated but subsequently inactivated in response to membrane depolarization. Here, we found that the mutation of an asparagine 533 residue (N533Q) in the outer pore loop region of PKD 2L1 caused a marked increase in outward currents induced by depolarization. In addition, the tail current analysis demonstrated that the N533Q mutants are activated during depolarization but the subsequent inactivation does not occur. Interestingly, the N533Q mutants lacked the channel activation triggered by the removal of stimuli such as extracellular alkalization and heating. Our findings suggest that the N533 residue in the outer pore loop region of PKD 2L1 has a key role in the voltage‐dependent channel inactivation.

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Transient Receptor Potential Channels and Endothelial Cell Calcium Signaling

Thakore

Earley

2019

Comprehensive Physiology

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The vascular endothelium is a broadly distributed and highly specialized organ. The endothelium has a number of functions including the control of blood vessels diameter through the production and release of potent vasoactive substances or direct electrical communication with underlying smooth muscle cells, regulates the permeability of the vascular barrier, stimulates the formation of new blood vessels, and influences inflammatory and thrombotic processes. Endothelial cells that make up the endothelium express a variety of cell-surface receptors and ion channels on the plasma membrane that are capable of detecting circulating hormones, neurotransmitters, oxygen tension, and shear stress across the vascular wall. Changes in these stimuli activate signaling cascades that initiate an appropriate physiological response. Increases in the global intracellular Ca 2+ concentration and localized Ca 2+ signals that occur within specialized subcellular microdomains are fundamentally important components of many signaling pathways in the endothelium. The transient receptor potential (TRP) channels are a superfamily of cationpermeable ion channels that act as a primary means of increasing cytosolic Ca 2+ in endothelial cells. Consequently, TRP channels are vitally important for the major functions of the endothelium. In this review, we provide an in-depth discussion of Ca 2+-permeable TRP channels in the endothelium and their role in vascular regulation.

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Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2)

Cited by 168 publications

References 74 publications

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

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

The asparagine 533 residue in the outer pore loop region of the mouse PKD2L1 channel is essential for its voltage‐dependent inactivation

Transient Receptor Potential Channels and Endothelial Cell Calcium Signaling

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