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Publication Abstract from PubMed

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 Ca(2+) nor any other metal ion was bound to wild type or variant KIBRA C2 in crystal structures, and Ca(2+) 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 beta-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.

Distinctive phosphoinositide and Ca(2+) binding properties of normal and cognitive performance-linked variant forms of KIBRA C2 domain.,Posner MG, Upadhyay A, Ishima R, Kalli AC, Harris G, Kremerskothen J, Sansom MSP, Crennell SJ, Bagby S J Biol Chem. 2018 May 3. pii: RA118.002279. doi: 10.1074/jbc.RA118.002279. PMID:29724824^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.