PKD1 Membrane Protein Introduction

Introduction of PKD1

Polycystin-1 (PKD1) is an extremely large protein with a high molecular mass exceeding 460 kDa and 11 predicted transmembrane spans. PKD1 is predicted to possess a large (~3,000 amino acid) extracellular N terminal domain and a short (~200 amino acid) C terminal domain that faces the cytoplasm. The massive PKD1 extracellular N terminal domain includes 16 copies of an Ig-like sequence known as the polycystin repeat. It also embodies a number of interesting molecular motifs that can participate in protein-protein interactions, supporting the suggestion that PKD1 may participate in cell-cell or cell-matrix associations. The extracellular domains of PKD1 and 2 may also sense fluid flow and pressure in the kidney. Relatives of PKD1 and 2 (PC1L3 and PC2L1) respond to acidic pH and may contribute to sour taste detection by the tongue, suggesting that PKD1 and 2 may similarly possess chemosensory properties.

Function of PKD1 Membrane Protein

PKD1 is implicated in a variety of pathways tied to proliferation, including G-protein signaling and the Wnt, AP-1, NFAT and JAK-STAT cascades. Moreover, depletion of PKD1 increases the rate of cell growth while its overexpression slows these processes, indicating that PKD1 may negatively regulate proliferation. Zebrafish express two PKD1 orthologues, PKD1a and PKD1b. The simultaneous morpholino-induced knockdown of PKD1a and PKD1b expression in zebrafish embryos produces a number of phenotypes, including pronephric duct cysts, hydrocephalus, and skeletal abnormalities. One of the most robust and readily quantifiable of these phenotypes is the development of upward-facing tail curvature. It is interesting to note that a similar tail curvature is also observed in zebrafish embryos that have been treated with inhibitors of γ-secretase. While the γ-secretase-dependent pathway that is responsible for this effect has not been fully elucidated, its similarity to the PKD1a and PKD1b morphant phenotype suggests that these two interventions may influence the same process. Support for this hypothesis derives from the observation that transgenic expression of a construct encoding the C terminal 200 amino acid residues of PKD1 is sufficient to at least partially rescue the tail curvature phenotypes that are produced by both PKD1a and PKD1b knockdown and by γ-secretase inhibition. These data lend in vivo supports to the concept that PKD1 C terminal tail cleavage is required in order to fulfill its biological functions and that a released fragment of the PKD1 C terminal tail is sufficient to recapitulate at least some of those functions.

Fig.1 Schematic diagram of PKD1 structure and cleavages. (Merrick, 2014)

Application of PKD1 Membrane Protein in Literature

1. Parnell S.C., et al. A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD. Hum Mol Genet. 2018, 27(19):3313-3324. PubMed ID: 29931260
   
   

   This article suggests that the role of Polycystin-1 is to activate G-protein signaling to regulate the Polycystin-1/2 calcium channel.

2. Verschuren E.H.J., et al. Polycystin-1 dysfunction impairs electrolyte and water handling in a renal pre-cystic mouse model for ADPKD. Am J Physiol Renal Physiol. 2018, 315(3):F537-F546. PubMed ID: 29767557
   
   

   These data indicate that PC1 is involved in renal Mg²⁺, Ca²⁺ and water handling, and its dysfunction resulting in a systemic electrolyte imbalance characterized by low serum electrolyte concentrations.

3. Zhang B., et al. Polycystin 1 loss of function is directly linked to an imbalance in G-protein signaling in the kidney. Development. 2018, 145(6). PubMed ID: 29530879
   
   

   This study supports the hypothesis that G proteins are recruited to the intracellular domain of PKD1 and that this interaction is crucial for its function in the kidney.

4. Lin C.C., et al. A cleavage product of Polycystin-1 is a mitochondrial matrix protein that affects mitochondria morphology and function when heterologously expressed. Sci Rep. 2018, 8(1):2743. PubMed ID: 29426897
   
   

   This article suggests that PC1 may play a direct role in regulating mitochondrial function and cellular metabolism and provides a framework to understand how impaired mitochondrial function could be linked to the regulation of tubular diameter in both physiological and pathological conditions.

5. Xiao Z., et al. Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis. J Clin Invest. 2018, 128(1):157-174. PubMed ID: 29202470
   
   

   This report indicates that polycystin-1/2 and TAZ integrate at the molecular level to reciprocally regulate osteoblast and adipocyte differentiation, indicating that polycystins/TAZ complex may be a potential therapeutic target to increase bone mass.

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Reference

1. Merrick D, et al. (2014). Polycystin-1 cleavage and the regulation of transcriptional pathways. Pediatr Nephrol. 29(4): 505-511.

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