Structural studies of the C‐terminal tail of polycystin‐2 (PC2) reveal insights into the mechanisms used for the functional regulation of PC2

Yang, Yifei; Ehrlich, Barbara E.

doi:10.1113/jp270933

Cited by 15 publications

(12 citation statements)

References 47 publications

(77 reference statements)

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“…TRPP2 is also known as polycystin-2 (PC2) or PKD2 and is permeable to Ca 2+ [ 125 ]. Mutations in TRPP2 is a cause of autosomal dominant polycystic kidney disease (ADPKD), a consequence thought to be due to aberrant calcium signaling of the mutated channel [ 126 ]. Understanding the interaction between TRPP2 and Ca 2+ is therefore important for elucidating the mechanisms of ADPKD.…”

Section: Trpp2mentioning

confidence: 99%

Ca2+ Regulation of TRP Ion Channels

Hasan

Zhang

2018

IJMS

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Ca2+ signaling influences nearly every aspect of cellular life. Transient receptor potential (TRP) ion channels have emerged as cellular sensors for thermal, chemical and mechanical stimuli and are major contributors to Ca2+ signaling, playing an important role in diverse physiological and pathological processes. Notably, TRP ion channels are also one of the major downstream targets of Ca2+ signaling initiated either from TRP channels themselves or from various other sources, such as G-protein coupled receptors, giving rise to feedback regulation. TRP channels therefore function like integrators of Ca2+ signaling. A growing body of research has demonstrated different modes of Ca2+-dependent regulation of TRP ion channels and the underlying mechanisms. However, the precise actions of Ca2+ in the modulation of TRP ion channels remain elusive. Advances in Ca2+ regulation of TRP channels are critical to our understanding of the diversified functions of TRP channels and complex Ca2+ signaling.

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Section: Trpp2mentioning

confidence: 99%

Ca2+ Regulation of TRP Ion Channels

Hasan

Zhang

2018

IJMS

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“…N-glycosylation in the exoplasmic domain of loop1 between the first and second transmembrane helices is essential for trafficking of PC2 to the Golgi apparatus and beyond 23 . Retention of PC2 in the early secretory pathway involves an ER retention signal 5 in the C-terminal domain 5 , which is adjacent to a downstream Ca 2+ binding EF-hand motif 24 and coiled-coil helices. While the coiled-coil regions are instrumental for complex formation and hetero-oligomerization 4,18,19,25,26 , the conformation of the EF-hand motif is essential for the ability to open the full-length PC2, and thus for Ca 2+ activation.…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2

Wilkes

Madej²,

Kreuter³

et al. 2017

Nat Struct Mol Biol

115

151

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Polycystin-2 (PC2), a calcium-activated cation TRP channel, is involved in diverse Ca signaling pathways. Malfunctioning Ca regulation in PC2 causes autosomal-dominant polycystic kidney disease. Here we report two cryo-EM structures of distinct channel states of full-length human PC2 in complex with lipids and cations. The structures reveal conformational differences in the selectivity filter and in the large exoplasmic domain (TOP domain), which displays differing N-glycosylation. The more open structure has one cation bound below the selectivity filter (single-ion mode, PC2), whereas multiple cations are bound along the translocation pathway in the second structure (multi-ion mode, PC2). Ca binding at the entrance of the selectivity filter suggests Ca blockage in PC2, and we observed density for the Ca-sensing C-terminal EF hand in the unblocked PC2 state. The states show altered interactions of lipids with the pore loop and TOP domain, thus reflecting the functional diversity of PC2 at different locations, owing to different membrane compositions.

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“…1b). In particular, this mutation truncates the coiled coil domain (aa 832–895) located in the C-terminal tail of TRPP2 that is crucial for the protein assembly and for its interaction with other calcium channels [21]. Consistently, R872X ADPKD2 T lymphocytes show reduced levels of intracellular calcium after ATP stimulation compared with those produced from CTRL subjects (Fig.…”

Section: Resultsmentioning

confidence: 90%

TRPP2 dysfunction decreases ATP-evoked calcium, induces cell aggregation and stimulates proliferation in T lymphocytes

et al. 2019

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Background Autosomal dominant polycystic kidney disease (ADPKD) is mainly characterised by the development and enlargement of renal cysts that lead to end-stage renal disease (ESRD) in adult patients. Other clinical manifestations of this pathology include hypertension, haematuria, abdominal pain, cardiovascular system alterations and intracranial aneurysms. ADPKD is linked to mutations in either PKD1 or PKD2 that codifies polycystin-1 (PC1) and polycystin-2 (PC2 or TRPP2), respectively. PC1 and TRPP2 are membrane proteins that function as receptor-channel elements able to regulate calcium homeostasis. The function of polycystins has been mainly studied in kidney cells; but the role of these proteins in T lymphocytes is not well defined. Methods T lymphocytes were produced from ADPKD1 and ADPKD2 patients as well as from non-ADPKD subjects undergoing renal replacement therapy (RRT) and healthy controls. Protein expression and phosphorylation levels were analysed by western blotting, cell proliferation was calculated by direct counting using trypan blue assay and intracellular calcium concentration was measured by Fura-2 method. Results PKD2 mutations lead to the significant reduction of TRPP2 expression in T lymphocytes derived from ADPKD patients. Furthermore, a smaller TRPP2 truncated protein in T lymphocytes of patients carrying the mutation R872X in PKD2 was also observed, suggesting that TRPP2 mutated proteins may be stably expressed. The silencing or mutation of PKD2 causes a strong reduction of ATP-evoked calcium in Jurkat cells and ADPKD2 T lymphocytes, respectively. Moreover, T lymphocytes derived from both ADPKD1 and ADPKD2 patients show increased cell proliferation, basal chemotaxis and cell aggregation compared with T lymphocytes from non-ADPKD subjects. Similarly to observations made in kidney cells, mutations in PKD1 and PKD2 dysregulate ERK, mTOR, NFkB and MIF pathways in T lymphocytes. Conclusions Because the alteration of ERK, mTOR, NFkB and MIF signalling found in T lymphocytes of ADPKD patients may contribute to the development of interstitial inflammation promoting cyst growth and kidney failure (ESRD), the targeting of inflammasome proteins could be an intriguing option to delay the progression of ADPKD.

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Structural studies of the C‐terminal tail of polycystin‐2 (PC2) reveal insights into the mechanisms used for the functional regulation of PC2

Cited by 15 publications

References 47 publications

Ca2+ Regulation of TRP Ion Channels

Ca2+ Regulation of TRP Ion Channels

Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2

TRPP2 dysfunction decreases ATP-evoked calcium, induces cell aggregation and stimulates proliferation in T lymphocytes

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