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

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

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