The STAT5b Linker Domain Mediates the Selectivity
of Catechol Bisphosphates for STAT5b over STAT5a
Version 2 2019-03-15, 20:19
Version 1 2019-03-15, 14:19
Posted on 2019-03-15 - 20:19
STAT family proteins
are important mediators of cell signaling
and represent therapeutic targets for the treatment of human diseases.
Most STAT inhibitors target the protein–protein interaction
domain, the SH2 domain, but specificity for a single STAT protein
is often limited. Recently, we developed catechol bisphosphates as
the first inhibitors of STAT5b demonstrated to exhibit a high degree
of selectivity over the close homologue STAT5a. Here, we show that
the amino acid in position 566 of the linker domain, not the SH2 domain,
is the main determinant of specificity. Arg566 in wild-type STAT5b
favors tight binding of catechol bisphosphates, while Trp566 in wild-type
STAT5a does not. Amino acid 566 also determines the affinity for a
tyrosine-phosphorylated peptide derived from the EPO receptor for
STAT5a and STAT5b, demonstrating the functional relevance of the STAT5
linker domain for the adjacent SH2 domain. These results provide the
first demonstration that a residue in the linker domain can determine
the affinity of nonpeptidic small-molecule inhibitors for the SH2
domain of STAT proteins. We propose targeting the interface between
the SH2 domain and linker domain as a novel design approach for the
development of potent and selective STAT inhibitors. In addition,
our data suggest that the linker domain could contribute to the enigmatically
divergent biological functions of the two STAT5 proteins.
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Gräb, Julian; Berg, Angela; Blechschmidt, Linda; Klüver, Barbara; Rubner, Stefan; Fu, Darwin Y.; et al. (2019). The STAT5b Linker Domain Mediates the Selectivity
of Catechol Bisphosphates for STAT5b over STAT5a. ACS Publications. Collection. https://doi.org/10.1021/acschembio.9b00137
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AUTHORS (9)
JG
Julian Gräb
AB
Angela Berg
LB
Linda Blechschmidt
BK
Barbara Klüver
SR
Stefan Rubner
DF
Darwin Y. Fu
JM
Jens Meiler
MG
Martin Gräber
TB
Thorsten Berg