Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment.
Date
2018-08-07ICR Author
Author
Xiong, S
Lorenzen, K
Couzens, AL
Templeton, CM
Rajendran, D
Mao, DYL
Juang, Y-C
Chiovitti, D
Kurinov, I
Guettler, S
Gingras, A-C
Sicheri, F
Type
Journal Article
Metadata
Show full item recordAbstract
The human NDR family kinases control diverse aspects of cell growth, and are regulated through phosphorylation and association with scaffolds such as MOB1. Here, we report the crystal structure of the human NDR1 kinase domain in its non-phosphorylated state, revealing a fully resolved atypically long activation segment that blocks substrate binding and stabilizes a non-productive position of helix αC. Consistent with an auto-inhibitory function, mutations within the activation segment of NDR1 dramatically enhance in vitro kinase activity. Interestingly, NDR1 catalytic activity is further potentiated by MOB1 binding, suggesting that regulation through modulation of the activation segment and by MOB1 binding are mechanistically distinct. Lastly, deleting the auto-inhibitory activation segment of NDR1 causes a marked increase in the association with upstream Hippo pathway components and the Furry scaffold. These findings provide a point of departure for future efforts to explore the cellular functions and the mechanism of NDR1.
Collections
Subject
Cell Line, Tumor
Epithelial Cells
Humans
Escherichia coli
Protein-Serine-Threonine Kinases
Hepatocyte Growth Factor
Adaptor Proteins, Signal Transducing
Microtubule-Associated Proteins
Proto-Oncogene Proteins
Recombinant Proteins
Crystallography, X-Ray
Cloning, Molecular
Sequence Alignment
Signal Transduction
Gene Expression
Gene Expression Regulation
Binding Sites
Amino Acid Sequence
Protein Binding
Sequence Homology, Amino Acid
Substrate Specificity
Kinetics
Mutation
Genetic Vectors
Models, Molecular
Protein Interaction Domains and Motifs
HEK293 Cells
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Research team
Structural Biology of Cell Signalling
Language
eng
Date accepted
2018-05-17
License start date
2018-08
Citation
Structure (London, England : 1993), 2018, 26 (8), pp. 1101 - 1115.e6
Publisher
CELL PRESS
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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