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Structure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca2+-dependent regulation of polycystin-2 channel activity.

The C-terminal cytoplasmic tail of polycystin-2 (PC2/TRPP2), a [Ca.sup.2+]-permeable channel, is frequently mutated or truncated in autosomal dominant polycystic kidney disease. We have previously shown that this tail consists of three functional regions: an EF-hand domain (PC2-EF, 720-797), a flexi... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America May 18, 2010, Vol.107(20), pp.9176-9181
Main Author: Petri, Edward T
Other Authors: Celic, Andjelka , Kennedy, Scott D , Ehrlich, Barbara E , Boggon, Titus J , Hodsdon, Michael E
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.0912295107
Link: http://search.proquest.com/docview/733500508/?pq-origsite=primo
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title: Structure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca2+-dependent regulation of polycystin-2 channel activity.
format: Article
creator:
  • Petri, Edward T
  • Celic, Andjelka
  • Kennedy, Scott D
  • Ehrlich, Barbara E
  • Boggon, Titus J
  • Hodsdon, Michael E
subjects:
  • Amino Acid Sequence–Metabolism
  • Calcium–Genetics
  • Conserved Sequence–Genetics
  • Ef Hand Motifs–Genetics
  • Humans–Metabolism
  • Models, Molecular–Chemistry
  • Molecular Sequence Data–Metabolism
  • Nuclear Magnetic Resonance, Biomolecular–Metabolism
  • Polycystic Kidney Diseases–Metabolism
  • Protein Conformation–Metabolism
  • Sequence Homology–Metabolism
  • Trpp Cation Channels–Metabolism
  • Trpp Cation Channels
  • Polycystic Kidney Disease 2 Protein
  • Calcium
ispartof: Proceedings of the National Academy of Sciences of the United States of America, May 18, 2010, Vol.107(20), pp.9176-9181
description: The C-terminal cytoplasmic tail of polycystin-2 (PC2/TRPP2), a [Ca.sup.2+]-permeable channel, is frequently mutated or truncated in autosomal dominant polycystic kidney disease. We have previously shown that this tail consists of three functional regions: an EF-hand domain (PC2-EF, 720-797), a flexible linker (798-827), and an oligomeric coiled coil domain (828-895). We found that PC2-EF binds [Ca.sup.2+] at a single site and undergoes [Ca.sup.2+]-dependent conformational changes, suggesting it is an essential element of [Ca.sup.2+]-sensitive regulation of PC2 activity. Here we describe the NMR structure and dynamics of [Ca.sup.2+]-bound PC2-EF. Human PC2-EF contains a divergent non-[Ca.sup.2+]-binding helix-loop-helix (HLH) motif packed against a canonical [Ca.sup.2+]-binding EF-hand motif. This HLH motif may have evolved from a canonical EF-hand found in invertebrate PC2 homologs. Temperature-dependent steady-state NOE experiments and NMR [R.sub.1] and [R.sub.2] relaxation rates correlate with increased molecular motion in the EF-hand, possibly due to exchange between apo and [Ca.sup.2+]-bound states, consistent with a role for PC2-EF as a [Ca.sup.2+]-sensitive regulator. Structure-based sequence conservation analysis reveals a conserved hydrophobic surface in the same region, which may mediate [Ca.sup.2+]-dependent protein interactions. We propose that [Ca.sup.2+]-sensing by PC2-EF is responsible for the cooperative nature of PC2 channel activation and inhibition. Based on our results, we present a mechanism of regulation of the [Ca.sup.2+] dependence of PC2 channel activity by PC2-EF. ion channel | NMR | polycystic kidney disease doi/ 10.1073/pnas.0912295107
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.0912295107
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleStructure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca2+-dependent regulation of polycystin-2 channel activity.
creatorPetri, Edward T ; Celic, Andjelka ; Kennedy, Scott D ; Ehrlich, Barbara E ; Boggon, Titus J ; Hodsdon, Michael E
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identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.0912295107
subjectAmino Acid Sequence–Metabolism ; Calcium–Genetics ; Conserved Sequence–Genetics ; Ef Hand Motifs–Genetics ; Humans–Metabolism ; Models, Molecular–Chemistry ; Molecular Sequence Data–Metabolism ; Nuclear Magnetic Resonance, Biomolecular–Metabolism ; Polycystic Kidney Diseases–Metabolism ; Protein Conformation–Metabolism ; Sequence Homology–Metabolism ; Trpp Cation Channels–Metabolism ; Trpp Cation Channels ; Polycystic Kidney Disease 2 Protein ; Calcium
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descriptionThe C-terminal cytoplasmic tail of polycystin-2 (PC2/TRPP2), a [Ca.sup.2+]-permeable channel, is frequently mutated or truncated in autosomal dominant polycystic kidney disease. We have previously shown that this tail consists of three functional regions: an EF-hand domain (PC2-EF, 720-797), a flexible linker (798-827), and an oligomeric coiled coil domain (828-895). We found that PC2-EF binds [Ca.sup.2+] at a single site and undergoes [Ca.sup.2+]-dependent conformational changes, suggesting it is an essential element of [Ca.sup.2+]-sensitive regulation of PC2 activity. Here we describe the NMR structure and dynamics of [Ca.sup.2+]-bound PC2-EF. Human PC2-EF contains a divergent non-[Ca.sup.2+]-binding helix-loop-helix (HLH) motif packed against a canonical [Ca.sup.2+]-binding EF-hand motif. This HLH motif may have evolved from a canonical EF-hand found in invertebrate PC2 homologs. Temperature-dependent steady-state NOE experiments and NMR [R.sub.1] and [R.sub.2] relaxation rates correlate with increased molecular motion in the EF-hand, possibly due to exchange between apo and [Ca.sup.2+]-bound states, consistent with a role for PC2-EF as a [Ca.sup.2+]-sensitive regulator. Structure-based sequence conservation analysis reveals a conserved hydrophobic surface in the same region, which may mediate [Ca.sup.2+]-dependent protein interactions. We propose that [Ca.sup.2+]-sensing by PC2-EF is responsible for the cooperative nature of PC2 channel activation and inhibition. Based on our results, we present a mechanism of regulation of the [Ca.sup.2+] dependence of PC2 channel activity by PC2-EF. ion channel | NMR | polycystic kidney disease doi/ 10.1073/pnas.0912295107
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titleStructure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca2+-dependent regulation of polycystin-2 channel activity.
authorPetri, Edward T ; Celic, Andjelka ; Kennedy, Scott D ; Ehrlich, Barbara E ; Boggon, Titus J ; Hodsdon, Michael E
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