The Polycystin-1, Lipoxygenase, and α-Toxin Domain Regulates Polycystin-1 Trafficking

Xu, Yaoxian; Streets, Andrew J.; Hounslow, Andrea M.; Tran, Uyen; Jean-Alphonse, Frédéric; Needham, Andrew J.; Vilardaga, Jean-Pierre; Wessely, Oliver; Williamson, Michael P.; Ong, Albert

doi:10.1681/asn.2014111074

Cited by 32 publications

(35 citation statements)

References 57 publications

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“…Mutation R3277C in the NTMD has been suggested to affect the folding, glycosylation, and trafficking of PKD1 (46). Mutation R3162C in PLAT or W414G in TOP PKD2 abrogates proper trafficking of PKD1 or PKD2, respectively (25,31). A few diseaserelated residues are mapped to the hydrophobic interior.…”

Section: Discussionmentioning

confidence: 99%

Structure of the human PKD1-PKD2 complex

et al. 2018

Science

214

206

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Mutations in two genes, and, account for most cases of autosomal dominant polycystic kidney disease, one of the most common monogenetic disorders. Here we report the 3.6-angstrom cryo-electron microscopy structure of truncated human PKD1-PKD2 complex assembled in a 1:3 ratio. PKD1 contains a voltage-gated ion channel (VGIC) fold that interacts with PKD2 to form the domain-swapped, yet noncanonical, transient receptor potential (TRP) channel architecture. The S6 helix in PKD1 is broken in the middle, with the extracellular half, S6a, resembling pore helix 1 in a typical TRP channel. Three positively charged, cavity-facing residues on S6b may block cation permeation. In addition to the VGIC, a five-transmembrane helix domain and a cytosolic PLAT domain were resolved in PKD1. The PKD1-PKD2 complex structure establishes a framework for dissecting the function and disease mechanisms of the PKD proteins.

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Section: Discussionmentioning

confidence: 99%

Structure of the human PKD1-PKD2 complex

et al. 2018

Science

214

206

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“…Surface localization of PC2 has also been shown to be regulated by GSK3-mediated phosphorylation at the N terminus (55). A recent study suggests that the PC1, lipoxygenase, alpha-toxin domain in the first intracellular loop of PC1 is involved in regulating PC1 trafficking and phosphorylation of a serine in this domain by PKA reduces PC1 localization on the plasma membrane as well as primary cilia, whereas a phosphodeficient mutation has normal cilia localization (58). Former studies have implied an association between PC1 phosphorylation status and its intracellular localization.…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin‐1 and regulates polycystin‐1 trafficking

Luo

et al. 2019

FASEB j.

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder causing renal failure. Mutations of polycystic kidney disease 1 (PKD1) account for most ADPKD cases. Defective ciliary localization of polycystin‐1 (PC1), a large integral membrane protein encoded by PKD1, underlies the pathogenesis of a subgroup of patients with ADPKD. However, the mechanisms by which PC1 and other ciliary proteins traffic to the primary cilium remain poorly understood. A ciliary targeting sequence (CTS) that resides in ciliary receptors is considered to function in the process. It has been reported that the VxP motif in the intracellular C‐terminal tail of PC1 functions as a CTS in an ADP ribosylation factor 4 (Arf4)/ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1)–dependent manner. However, other recent studies have revealed that this motif is dispensable for PC1 trafficking to cilia. In this study, we identified a novel CTS consisting of 8 residues (RHKVRFEG) in the PC1 C tail. We found that this motif is sufficient to bind protein phosphatase 1 (PP1)α, a ubiquitously expressed phosphatase in the phosphoprotein phosphatase (PPP) family. Mutations in this CTS motif disrupt binding with PP1α and impair ciliary localization of PC1. Additionally, short hairpin RNA–mediated knockdown of PP1α results in reduced ciliary localization of PC1 and elongated cilia, suggesting a role for PP1α in the regulation of ciliary structure and function.—Luo, C., Wu, M., Su, X., Yu, F., Brautigan, D. L., Chen, J., Zhou, J. Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin‐1 and regulates polycystin‐1 trafficking. FASEB J. 33, 9945–9958 (2019). http://www.fasebj.org

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“…The absence of either polycystin protein from the primary cilium is sufficient to promote kidney cystogenesis, and a number of PKD1 and PKD2 mutants that are defective in ciliary trafficking are reported to be pathogenic (Ma et al, 2013;Cai et al, 2014;Su et al, 2015). Several studies have therefore addressed the question of how PC1 and PC2 traffic to the primary cilium from compartments of the biosynthetic membrane trafficking network, with roles for PC1-PC2 complex formation, cleavage of PC1 at a juxtamembrane GPCR autoproteolytic site, VxP ciliary targeting motifs, an internal PLAT domain in PC1 and Rabep1-GGA1-Arl3, BBSome and exocyst trafficking modules having all been implicated (Hanaoka et al, 2000;Geng et al, 2006;Kim et al, 2014;Fogelgren et al, 2011;Su et al, 2014;Su et al, 2015;Xu et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Retromer associates with the cytoplasmic amino-terminus of polycystin-2

Tilley

Gallon

Luo

et al. 2018

Journal of Cell Science

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic human disease, with around 12.5 million people affected worldwide. ADPKD results from mutations in either or, which encode the atypical G-protein coupled receptor polycystin-1 (PC1) and the transient receptor potential channel polycystin-2 (PC2), respectively. Although altered intracellular trafficking of PC1 and PC2 is an underlying feature of ADPKD, the mechanisms which govern vesicular transport of the polycystins through the biosynthetic and endosomal membrane networks remain to be fully elucidated. Here, we describe an interaction between PC2 and retromer, a master controller for the sorting of integral membrane proteins through the endo-lysosomal network. We show that association of PC2 with retromer occurs via a region in the PC2 cytoplasmic amino-terminal domain, independently of the retromer-binding Wiskott-Aldrich syndrome and scar homologue (WASH) complex. Based on observations that retromer preferentially interacts with a trafficking population of PC2, and that ciliary levels of PC1 are reduced upon mutation of key residues required for retromer association in PC2, our data are consistent with the identification of PC2 as a retromer cargo protein.This article has an associated First Person interview with the first author of the paper.

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The Polycystin-1, Lipoxygenase, and α-Toxin Domain Regulates Polycystin-1 Trafficking

Cited by 32 publications

References 57 publications

Structure of the human PKD1-PKD2 complex

Structure of the human PKD1-PKD2 complex

Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin‐1 and regulates polycystin‐1 trafficking

Retromer associates with the cytoplasmic amino-terminus of polycystin-2

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