6 research outputs found
Domain-Swapping Switch Point in Ste20 Protein Kinase SPAK
The related protein kinases SPAK
and OSR1 regulate ion homeostasis
in part by phosphorylating cation cotransporter family members. The
structure of the kinase domain of OSR1 was determined in the unphosphorylated
inactive form and, like some other Ste20 kinases, exhibited a domain-swapped
activation loop. To further probe the role of domain swapping in SPAK
and OSR1, we have determined the crystal structures of SPAK 63–403
at 3.1 Å and SPAK 63–390 T243D at 2.5 Å resolution.
These structures encompass the kinase domain and different portions
of the C-terminal tail, the longer without and the shorter with an
activating T243D point mutation. The structure of the T243D protein
reveals significant conformational differences relative to unphosphorylated
SPAK and OSR1 but also has some features of an inactive kinase. Both
structures are domain-swapped dimers. Sequences involved in domain
swapping were identified and mutated to create a SPAK monomeric mutant
with kinase activity, indicating that monomeric forms are active.
The monomeric mutant is activated by WNK1 but has reduced activity
toward its substrate NKCC2, suggesting regulatory roles for domain
swapping. The structure of partially active SPAK T243D is consistent
with a multistage activation process in which phosphorylation induces
a SPAK conformation that requires further remodeling to build the
active structure
Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β‑Cells
Novel strategies are needed to modulate
β-cell differentiation
and function as potential β-cell replacement or restorative
therapies for diabetes. We previously demonstrated that small molecules
based on the isoxazole scaffold drive neuroendocrine phenotypes. The
nature of the effects of isoxazole compounds on β-cells was
incompletely defined. We find that isoxazole induces genes that support
neuroendocrine and β-cell phenotypes and suppresses genes important
for proliferation. Isoxazole alters β-cell metabolites and protects
glucose-responsive signaling pathways under lipotoxic conditions.
Finally, we show that isoxazole improves glycemia in a mouse model
of β-cell regeneration. Isoxazole is a prime candidate to alter
cell fate in different contexts
Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β‑Cells
Novel strategies are needed to modulate
β-cell differentiation
and function as potential β-cell replacement or restorative
therapies for diabetes. We previously demonstrated that small molecules
based on the isoxazole scaffold drive neuroendocrine phenotypes. The
nature of the effects of isoxazole compounds on β-cells was
incompletely defined. We find that isoxazole induces genes that support
neuroendocrine and β-cell phenotypes and suppresses genes important
for proliferation. Isoxazole alters β-cell metabolites and protects
glucose-responsive signaling pathways under lipotoxic conditions.
Finally, we show that isoxazole improves glycemia in a mouse model
of β-cell regeneration. Isoxazole is a prime candidate to alter
cell fate in different contexts
Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β‑Cells
Novel strategies are needed to modulate
β-cell differentiation
and function as potential β-cell replacement or restorative
therapies for diabetes. We previously demonstrated that small molecules
based on the isoxazole scaffold drive neuroendocrine phenotypes. The
nature of the effects of isoxazole compounds on β-cells was
incompletely defined. We find that isoxazole induces genes that support
neuroendocrine and β-cell phenotypes and suppresses genes important
for proliferation. Isoxazole alters β-cell metabolites and protects
glucose-responsive signaling pathways under lipotoxic conditions.
Finally, we show that isoxazole improves glycemia in a mouse model
of β-cell regeneration. Isoxazole is a prime candidate to alter
cell fate in different contexts
Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β‑Cells
Novel strategies are needed to modulate
β-cell differentiation
and function as potential β-cell replacement or restorative
therapies for diabetes. We previously demonstrated that small molecules
based on the isoxazole scaffold drive neuroendocrine phenotypes. The
nature of the effects of isoxazole compounds on β-cells was
incompletely defined. We find that isoxazole induces genes that support
neuroendocrine and β-cell phenotypes and suppresses genes important
for proliferation. Isoxazole alters β-cell metabolites and protects
glucose-responsive signaling pathways under lipotoxic conditions.
Finally, we show that isoxazole improves glycemia in a mouse model
of β-cell regeneration. Isoxazole is a prime candidate to alter
cell fate in different contexts
Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β‑Cells
Novel strategies are needed to modulate
β-cell differentiation
and function as potential β-cell replacement or restorative
therapies for diabetes. We previously demonstrated that small molecules
based on the isoxazole scaffold drive neuroendocrine phenotypes. The
nature of the effects of isoxazole compounds on β-cells was
incompletely defined. We find that isoxazole induces genes that support
neuroendocrine and β-cell phenotypes and suppresses genes important
for proliferation. Isoxazole alters β-cell metabolites and protects
glucose-responsive signaling pathways under lipotoxic conditions.
Finally, we show that isoxazole improves glycemia in a mouse model
of β-cell regeneration. Isoxazole is a prime candidate to alter
cell fate in different contexts