Distinctive phosphoinositide- A nd Ca 2+-binding properties of normal and cognitive performance-linked variant forms of KIBRA C2 domain

Mareike G Posner, Abhishek Upadhyay, Rieko Ishima, Antreas C Kalli, Gemma Harris, Joachim Kremerskothen, Mark S P Sansom, Susan J Crennell, Stefan Bagby

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Kidney- A nd brain-expressed protein (KIBRA), a multifunctional scaffold protein with around 20 known binding partners, is involved in memory and cognition, organ size control via the Hippo pathway, cell polarity, and membrane trafficking. KIBRA includes tandem N-terminal WW domains, a C 2+ domain, and motifs for binding atypical PKC and PDZ domains. A naturally occurring human KIBRA variant involving residue changes at positions 734 (Met-to-Ile) and 735 (Ser-to-Ala) within the C 2+ domain affects cognitive performance. We have elucidated 3D structures and calcium- A nd phosphoinositide-binding properties of human KIBRA C 2+ domain. BothWT and variant C 2+ adopt a canonical type I topology C 2+ domain fold. Neither Ca2 nor any other metal ion was bound to WT or variant KIBRA C 2+ in crystal structures, and Ca2 titration produced no significant reproducible changes in NMR spectra. NMR and X-ray diffraction data indicatethat KIBRA C 2+ binds phosphoinositides via an atypical site involving β-strands 5, 2, 1, and 8.Molecular dynamics simulations indicate that KIBRA C 2+ interacts with membranes via primary and secondary sites on the same domain face as the experimentally identified phosphoinositide-binding site. Our results indicate that KIBRA C 2+ domain association with membranes is calcium-independent and involves distinctive C 2+ domain-membrane relative orientations.

Original languageEnglish
Pages (from-to)9335-9344
Number of pages10
JournalThe Journal of biological chemistry
Volume293
Issue number24
Early online date3 May 2018
DOIs
Publication statusPublished - 15 Jun 2018

Fingerprint

Phosphatidylinositols
Membranes
Nuclear magnetic resonance
Calcium
Titration
Scaffolds
PDZ Domains
Metal ions
Molecular dynamics
Cell Polarity
Organ Size
Crystal structure
Binding Sites
Topology
Association reactions
Molecular Dynamics Simulation
Data storage equipment
X-Ray Diffraction
X ray diffraction
Cognition

Keywords

  • Journal Article
  • C2 Domains
  • Humans
  • Models, Molecular
  • Crystallography, X-Ray
  • Phosphoproteins/chemistry
  • Calcium/metabolism
  • Phosphatidylinositols/metabolism
  • Intracellular Signaling Peptides and Proteins/chemistry
  • Cell Membrane/metabolism
  • Protein Binding
  • Protein Conformation
  • Polymorphism, Single Nucleotide

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Cite this

Distinctive phosphoinositide- A nd Ca 2+-binding properties of normal and cognitive performance-linked variant forms of KIBRA C2 domain. / Posner, Mareike G; Upadhyay, Abhishek; Ishima, Rieko; Kalli, Antreas C; Harris, Gemma; Kremerskothen, Joachim; Sansom, Mark S P; Crennell, Susan J; Bagby, Stefan.

In: The Journal of biological chemistry, Vol. 293, No. 24, 15.06.2018, p. 9335-9344.

Research output: Contribution to journalArticle

Posner, Mareike G ; Upadhyay, Abhishek ; Ishima, Rieko ; Kalli, Antreas C ; Harris, Gemma ; Kremerskothen, Joachim ; Sansom, Mark S P ; Crennell, Susan J ; Bagby, Stefan. / Distinctive phosphoinositide- A nd Ca 2+-binding properties of normal and cognitive performance-linked variant forms of KIBRA C2 domain. In: The Journal of biological chemistry. 2018 ; Vol. 293, No. 24. pp. 9335-9344.
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AU - Kremerskothen, Joachim

AU - Sansom, Mark S P

AU - Crennell, Susan J

AU - Bagby, Stefan

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AB - Kidney- A nd brain-expressed protein (KIBRA), a multifunctional scaffold protein with around 20 known binding partners, is involved in memory and cognition, organ size control via the Hippo pathway, cell polarity, and membrane trafficking. KIBRA includes tandem N-terminal WW domains, a C 2+ domain, and motifs for binding atypical PKC and PDZ domains. A naturally occurring human KIBRA variant involving residue changes at positions 734 (Met-to-Ile) and 735 (Ser-to-Ala) within the C 2+ domain affects cognitive performance. We have elucidated 3D structures and calcium- A nd phosphoinositide-binding properties of human KIBRA C 2+ domain. BothWT and variant C 2+ adopt a canonical type I topology C 2+ domain fold. Neither Ca2 nor any other metal ion was bound to WT or variant KIBRA C 2+ in crystal structures, and Ca2 titration produced no significant reproducible changes in NMR spectra. NMR and X-ray diffraction data indicatethat KIBRA C 2+ binds phosphoinositides via an atypical site involving β-strands 5, 2, 1, and 8.Molecular dynamics simulations indicate that KIBRA C 2+ interacts with membranes via primary and secondary sites on the same domain face as the experimentally identified phosphoinositide-binding site. Our results indicate that KIBRA C 2+ domain association with membranes is calcium-independent and involves distinctive C 2+ domain-membrane relative orientations.

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