Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases

Details

Serval ID
serval:BIB_5FC4BE935F17
Type
Article: article from journal or magazin.
Collection
Publications
Title
Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases
Journal
Mol Cell
Author(s)
Zhou Y. J., Chen M., Cusack N. A., Kimmel L. H., Magnuson K. S., Boyd J. G., Lin W., Roberts J. L., Lengi A., Buckley R. H., Geahlen R. L., Candotti F., Gadina M., Changelian P. S., O'Shea J. J.
ISSN
1097-2765 (Print)
ISSN-L
1097-2765
Publication state
Published
Issued date
11/2001
Peer-reviewed
Oui
Volume
8
Number
5
Pages
959-69
Language
english
Notes
Zhou, Y J
Chen, M
Cusack, N A
Kimmel, L H
Magnuson, K S
Boyd, J G
Lin, W
Roberts, J L
Lengi, A
Buckley, R H
Geahlen, R L
Candotti, F
Gadina, M
Changelian, P S
O'Shea, J J
eng
Mol Cell. 2001 Nov;8(5):959-69.
Abstract
Janus kinases comprise carboxyterminal kinase, pseudokinase, SH2-like, and N-terminal FERM domains. We identified three patient-derived mutations in the FERM domain of Jak3 and investigated the functional consequences of these mutations. These mutations inhibited receptor binding and also abrogated kinase activity, suggesting interactions between the FERM and kinase domains. In fact, the domains were found to physically associate, and coexpression of the FERM domain enhanced activity of the isolated kinase domain. Conversely, staurosporine, which alters kinase domain structure, disrupted receptor binding, even though the catalytic activity of Jak3 is dispensable for receptor binding. Thus, the Jak FERM domain appears to have two critical functions: receptor interaction and maintenance of kinase integrity.
Keywords
Adenosine Triphosphate/analogs & derivatives/metabolism, Amino Acid Sequence, Animals, COS Cells, Catalysis, Enzyme Inhibitors/pharmacology, Humans, Interleukin Receptor Common gamma Subunit, Janus Kinase 3, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Protein Structure, Tertiary, Protein-Tyrosine Kinases/chemistry/genetics/*metabolism, Pyrimidines/pharmacology, Receptors, Interleukin-7/genetics/metabolism, Recombinant Fusion Proteins/chemistry/metabolism, Sequence Alignment, Staurosporine/pharmacology, src-Family Kinases/antagonists & inhibitors
Pubmed
Create date
01/11/2017 10:29
Last modification date
20/08/2019 14:17
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