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

Posner, MG and Upadhyay, A and Ishima, R and Kalli, AC and Harris, G and Kremerskothen, J and Sansom, MSP and Crennell, SJ and Bagby, S (2018) Distinctive phosphoinositide- A nd Ca<sup>2+</sup>-binding properties of normal and cognitive performance-linked variant forms of KIBRA C2 domain. Journal of Biological Chemistry, 293 (24). pp. 9335-9344. ISSN 0021-9258

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Abstract

© 2018 Michalski and Williams Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. 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 C2+ 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 C2+ domain affects cognitive performance. We have elucidated 3D structures and calcium- A nd phosphoinositide-binding properties of human KIBRA C2+ domain. BothWT and variant C2+ adopt a canonical type I topology C2+ domain fold. Neither Ca2 nor any other metal ion was bound to WT or variant KIBRA C2+ in crystal structures, and Ca2 titration produced no significant reproducible changes in NMR spectra. NMR and X-ray diffraction data indicatethat 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.

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