Johns Hopkins scientists were dubious in the early
1980s when they stumbled on small sugar
molecules lurking in the centers of cells; not only were
the molecules not supposed to be there, but
they certainly weren't supposed to be repeatedly attaching
to and detaching from proteins,
effectively switching them on and off. The conventional
wisdom was that the job of turning proteins
on and off — and thus determining their actions
— fell to phosphates, in a common and easy-to-detect
chemical step in which phosphates fasten to and unfasten
from proteins, a process called
phosphorylation.
Now, after decades of investigating the "new"
sugar-based protein modification they
discovered, the Johns Hopkins scientists admit that they
themselves were surprised by their latest
results. Published recently in the Proceedings of the
National Academy of Sciences, their findings
show that the surreptitious sugar switch is likely as
influential and ubiquitous as its phosphate
counterpart and, indeed, even plays a role in regulating
phosphorylation itself.
More to the point, the work has implications for
finding new treatments for a number of
diseases such as diabetes, neurodegeneration and cancer,
because the new switches form yet another
potential target for manipulation by drugs.
"Like dark matter in the cosmos, it's hard to find
even though it's very abundant," said Gerald
Hart, the DeLamar Professor and director of
Biological
Chemistry at the Johns Hopkins School of
Medicine, referring to the sugar — O-GlcNAc
(oh-GLIK'-nak) — that carries out GlcNAcylation.
For years, Hart's team thought of GlcNAcylation as
phosphorylation's foil, a simple, classic case
of either-or. New technologies involving molecular
sleuthing with a mass spectrometer allowed them to
measure the extent to which the addition of sugar to
proteins affects phosphorylation.
Of 428 sites on which phosphate was being added to and
taken off of proteins, all responded in
some way to increased O-GlcNAc: 280 decreased
phosphorylation, and 148 increased phosphorylation.
"The influence of sugar is striking," Hart said. "The
presence of O-GlcNAc causes the enzymes
that add the phosphate to do something different, and this
cross-talk itself can modify proteins."
Because both sugar and phosphate modifications are
linked to how cells work, they are
fundamental to the understanding and eventual control of
the molecular processes that underlie many
diseases.
"With regard to cancer, diabetes and Alzheimer's,"
Hart said, "most people in the world today
have been studying the yang [phosphorylation] but not the
yin [GlcNAcylation]. There's another whole
side that people were unaware of where diabetes diagnostics
and cancer therapies could be targeted."
The research was funded by the National Institutes of
Health. Authors on the paper are Zihao
Wang, Marjan Gucek and Hart, all of Johns Hopkins.
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