Differences in the dynamics of the tandem‐SH2 modules of the Syk and ZAP ‐70 tyrosine kinases

Autor: Neel H. Shah, Christine L. Gee, John Kuriyan, Jean M. Badroos, Helen T. Hobbs, Susan Marqusee
Rok vydání: 2021
Předmět:
Protein Conformation
alpha-Helical
Conformational change
Full‐Length Papers
T-Lymphocytes
Genetic Vectors
Gene Expression
Syk
chemical and pharmacologic phenomena
Adaptive Immunity
Molecular Dynamics Simulation
Crystallography
X-Ray
SH2 domain
Biochemistry
Full‐Length Paper
evolution
Immunoreceptor tyrosine-based activation motif
Escherichia coli
Animals
Humans
Syk Kinase
Protein Interaction Domains and Motifs
Cloning
Molecular
Tyrosine
Molecular Biology
B-Lymphocytes
Binding Sites
ZAP-70 Protein-Tyrosine Kinase
Chemistry
conformational landscape
hydrogen–deuterium exchange mass spectrometry
tyrosine kinase signaling
Deuterium Exchange Measurement
hemic and immune systems
Biological Evolution
Recombinant Proteins
Protein kinase domain
protein dynamics
Biophysics
Phosphorylation
Protein Conformation
beta-Strand
Tyrosine kinase
Protein Binding
Signal Transduction
Zdroj: Protein Science : A Publication of the Protein Society
ISSN: 1469-896X
0961-8368
DOI: 10.1002/pro.4199
Popis: The catalytic activity of Syk‐family tyrosine kinases is regulated by a tandem Src homology 2 module (tSH2 module). In the autoinhibited state, this module adopts a conformation that stabilizes an inactive conformation of the kinase domain. The binding of the tSH2 module to phosphorylated immunoreceptor tyrosine‐based activation motifs necessitates a conformational change, thereby relieving kinase inhibition and promoting activation. We determined the crystal structure of the isolated tSH2 module of Syk and find, in contrast to ZAP‐70, that its conformation more closely resembles that of the peptide‐bound state, rather than the autoinhibited state. Hydrogen–deuterium exchange by mass spectrometry, as well as molecular dynamics simulations, reveal that the dynamics of the tSH2 modules of Syk and ZAP‐70 differ, with most of these differences occurring in the C‐terminal SH2 domain. Our data suggest that the conformational landscapes of the tSH2 modules in Syk and ZAP‐70 have been tuned differently, such that the autoinhibited conformation of the Syk tSH2 module is less stable. This feature of Syk likely contributes to its ability to more readily escape autoinhibition when compared to ZAP‐70, consistent with tighter control of downstream signaling pathways in T cells.
PDB Code(s): 7SA7
Databáze: OpenAIRE
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