Projects per year
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 language | English |
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Pages (from-to) | 9335-9344 |
Number of pages | 10 |
Journal | The Journal of biological chemistry |
Volume | 293 |
Issue number | 24 |
Early online date | 3 May 2018 |
DOIs | |
Publication status | Published - 15 Jun 2018 |
Bibliographical note
© 2018 Posner et al.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
Fingerprint
Dive into the research topics of 'Distinctive phosphoinositide- A nd Ca 2+-binding properties of normal and cognitive performance-linked variant forms of KIBRA C2 domain'. Together they form a unique fingerprint.Projects
- 1 Finished
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Structural, Biochemical and Computational Studies of KIBRA Protein-Protein and Membrane Interactions
Bagby, S. (PI) & Van Den Elsen, J. (CoI)
Biotechnology and Biological Sciences Research Council
1/08/12 → 29/01/16
Project: Research council
Profiles
-
Stefan Bagby
- Department of Life Sciences - Reader
- Centre for Nanoscience and Nanotechnology
- Centre for Bioengineering & Biomedical Technologies (CBio)
Person: Research & Teaching, Affiliate staff