Posner, MG, Upadhyay, A, Ishima, R et al. (6 more authors) (2018) Distinctive phosphoinositide- and Ca²⁺-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
Abstract
Kidney- and 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- and phosphoinositide-binding properties of human KIBRA C2 domain. Both WT 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 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.
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Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 Posner et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. This research was originally published in the Journal of Biological Chemistry. Posner, MG, Upadhyay, A, Ishima, R et al. Distinctive phosphoinositide- and Ca²⁺-binding properties of normal and cognitive performance–linked variant forms of KIBRA C2 domain. J. Biol. Chem. 2018; 293: 9335-9344. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | nuclear magnetic resonance (NMR); crystallography; phosphoinositide; molecular dynamics; analytical ultracentrifugation; calcium-binding protein; Alzheimer disease; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR); Hippo pathway; membrane trafficking; C2 domain; human cognition; KIBRA; WWC protein family |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) |
Depositing User: | Symplectic Publications |
Date Deposited: | 18 May 2018 12:27 |
Last Modified: | 07 May 2019 14:29 |
Status: | Published |
Publisher: | American Society for Biochemistry and Molecular Biology |
Identification Number: | 10.1074/jbc.RA118.002279 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:131014 |