A novel PKD2L1 C-terminal domain critical for trimerization and channel function

Zheng, Wang; Hussein, Shaimaa; Yang, Jungwoo; Huang, Jun; Zhang, Fan; Hernandez-Anzaldo, Samuel; Fernández-Patrón, Carlos; Zeng, Hongbo; Tang, Jingfeng; Chen, Xing-Zhen

doi:10.1038/srep09460

Cited by 12 publications

(11 citation statements)

References 45 publications

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“…C-terminal coiled-coil domain (26 -29, 41), the N terminus (32), and a cysteine residue in the outer pore region (Cys 632 ) (31) were all found to play roles in TRPP2 homomeric assembly. In TRPP3, a homologous C-terminal coiled-coil domain and a C1 domain, which is located upstream of the coiled-coil domain, have been shown to be essential for its homomeric assembly (25,38). The TRPP2 coiled-coil domain is also directly involved in binding to the C-terminal coiled-coil domain of PKD1 and plays a key role in the TRPP2-PKD1 complex assembly (26,27,29,30,41).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Capped synthetic RNA of TRPV6, TRPV5, TRPV4, TRPC4, and TRPM8 were synthesized by in vitro transcription with mMessage mMachine Kit (Ambion, Austin, TX, USA) and injected (25–50 ng/oocyte) into Xenopus laevis oocytes prepared as described in Zheng et al (35). Equal volumes of water were injected into control oocytes.…”

Section: Methodsmentioning

confidence: 99%

Identification and characterization of hydrophobic gate residues in TRP channels

Zheng

Cai

et al. 2018

FASEB j.

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Transient receptor potential (TRP) channels, subdivided into 6 subfamilies in mammals, have essential roles in sensory physiology. They respond to remarkably diverse stimuli, comprising thermal, chemical, and mechanical modalities, through opening or closing of channel gates. In this study, we systematically substituted the hydrophobic residues within the distal fragment of pore-lining helix S6 with hydrophilic residues and, based on Xenopus oocyte and mammalian cell electrophysiology and a hydrophobic gate theory, identified hydrophobic gates in TRPV6/V5/V4/C4/M8. We found that channel activity drastically increased when TRPV6 or TRPV5, but not any of their adjacent residues, was substituted with hydrophilic residues. Channel activity strongly correlated with the hydrophilicity of the residues at those sites, suggesting that consecutive hydrophobic residues TRPV6 and TRPV5 form a double-residue gate in each channel. By the same strategy, we identified a hydrophobic single-residue gate in TRPV4, TRPC4, and TRPM8. In support of the hydrophobic gate theory, hydrophilic substitution at the gate site, which removes the hydrophobic gate seal, substantially increased the activity of TRP channels in low-activity states but had little effect on the function of activated channels. The double-residue gate channels were more sensitive to small changes in the gate's hydrophobicity or size than single-residue gate channels. The unconventional double-reside gating mechanism in TRP channels may have been evolved to respond especially to physiologic stimuli that trigger relatively small gate conformational changes.-Zheng, W., Hu, R., Cai, R., Hofmann, L., Hu, Q., Fatehi, M., Long, W., Kong, T., Tang, J., Light, P., Flockerzi, V., Cao, Y., Chen, X.-Z. Identification and characterization of hydrophobic gate residues in TRP channels.

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“…Another signal, extracellular Ca 2+ , might also act as the stimulus that activates PKD2-L1 in taste cells or primary cilia as postulated Tordoff, 2001). Indeed, exposure to high concentrations of extracellular Ca 2+ ([Ca 2+ ] o ) was reported to activate homomeric PKD2-L1 channels reconstituted in Xenopus oocytes, giving rise to an inward Ca 2+ current that displayed inactivation (Chen et al, 1999;Zheng et al, 2015). Unfortunately, such Ca 2+ -activated Ca 2+ current (I Ca ) responses have not been observed for either homomeric or heteromeric PKD2-L1 channels overexpressed in mammalian cells .…”

Section: Introductionmentioning

confidence: 99%

Influx-Operated Ca 2+ Entry via PKD2-L1 and PKD1-L3 Channels Facilitates Sensory Responses to Polymodal Transient Stimuli

Liu

et al. 2015

Cell Reports

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The polycystic TRP subfamily member PKD2-L1, in complex with PKD1-L3, is involved in physiological responses to diverse stimuli. A major challenge to understanding whether and how PKD2-L1/PKD1-L3 acts as a bona fide molecular transducer is that recombinant channels usually respond with small or undetectable currents. Here, we discover a type of Ca(2+) influx-operated Ca(2+) entry (ICE) that generates pronounced Ca(2+) spikes. Triggered by rapid onset/offset of Ca(2+), voltage, or acid stimuli, Ca(2+)-dependent activation amplifies a small Ca(2+) influx via the channel. Ca(2+) concurrently drives a self-limiting negative feedback (Ca(2+)-dependent inactivation) that is regulated by the Ca(2+)-binding EF hands of PKD2-L1. Our results suggest a biphasic ICE with opposite Ca(2+) feedback regulation that facilitates sensory responses to multimodal transient stimuli. We suggest that such a mechanism may also occur for other sensory modalities and other Ca(2+) channels.

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A novel PKD2L1 C-terminal domain critical for trimerization and channel function

Cited by 12 publications

References 45 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

Identification and characterization of hydrophobic gate residues in TRP channels

Influx-Operated Ca 2+ Entry via PKD2-L1 and PKD1-L3 Channels Facilitates Sensory Responses to Polymodal Transient Stimuli

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