Distinctive phosphoinositide- A and Ca2+ 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

KIBRA, a multi-functional scaffold protein with around twenty 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 C2 domain and motifs for binding aPKC and PDZ domains. A naturally occurring human KIBRA variant involving residue changes at positions 734 (M-to-I) and 735 (S-to-A) within the C2 domain affects cognitive performance. We have elucidated 3D structures, and calcium and phosphoinositide binding properties, of human KIBRA C2 domain. Both wild type and variant C2 adopt a canonical type I topology C2 domain fold. Neither Ca2+ nor any other metal ion was bound to wild type or variant KIBRA C2 in crystal structures, and Ca2+ titration produced no significant reproducible changes in NMR spectra. NMR and X-ray diffraction data indicate that KIBRA C2 binds phosphoinositides via an atypical site involving β-strands 5, 2, 1, and 8. Molecular dynamics simulations indicate that KIBRA C2 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 C2 domain association with membranes is calcium-independent and involves distinctive C2 domain-membrane relative orientations.

LanguageEnglish
Pages9335-9344
JournalThe Journal of biological chemistry
Volume293
Issue number24
Early online date3 May 2018
DOIs
StatusPublished - 15 Jun 2018

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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

Cite this

Distinctive phosphoinositide- A and Ca2+ 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 and Ca2+ 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 - Ishima, Rieko

AU - Kalli, Antreas C

AU - Harris, Gemma

AU - Kremerskothen, Joachim

AU - Sansom, Mark S P

AU - Crennell, Susan J

AU - Bagby, Stefan

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