Page 15 - Abacoa Community News - July '22

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Scripps Research from page 14 researchers to study systematically how the function of a
proteoglycan changes as its GAG arrangement changes.
These molecules The researchers also developed techniques allowing
are often thickly them to anchor their proteoglycans in cell membranes
present on the surfaces or to let them float freely, to see how this affects
of cells and are known proteoglycans’ functions in different circumstances.
to have a broad set Using their synthetic versions of common proteoglycans
of functions in the called syndecans, the scientists were able to study the
body, though how respective contributions of GAG chains and core proteins.
they work and how Specifically, they looked at two key biological processes
their dysfunctions mediated by syndecans: the maturing of stem cells, and the
contribute to diseases Semi-synthetic syndecan-1 spreading of breast cancer cells on an extracellular matrix.
are largely mysteries. proteoglycan rescues the “We learned from these experiments that not only
Sem i -synt he t ic maturation of mouse embryonic Scripps Research scientists developed a method to build and the GAG chains but also the core proteins contribute to
syndecan-1 proteoglycan stem cells into neural precursor test sugared proteins called proteoglycans to understand proteoglycan function,” says Critcher. “Notably, we also
rescues the maturation cells (red and green). Photo by their role in health and disease. Envisioned as a factory found that proteoglycans’ role in cancer cell spreading
of mouse embryonic Meg Critcher, Scripps Research production line, mammalian CHO-S and E. coli are fed depends heavily on whether they are anchored to the cell
stem cells into neural chemical compounds to produce glycosaminoglycans and membrane or free-floating.”
precursor cells (red and green). Credit: Meg Critcher, sydecan-1 core proteins. These modules are then selectively The team also incorporated a method called proximity
Scripps Research conjugated through a method called “click chemistry” tagging to help them identify proteoglycans’ interaction
The scientists, who reported their work in Nature (CuAAC) to complete the semi-synthetic proteoglycan, which partners. Huang and colleagues are now using this,
Chemical Biology on May 12, devised synthetic can be attached to cell surfaces. Photo by Meg Critcher, and their modular construction technique, to study the
proteoglycans that closely mimic real ones but have Scripps Research interactions of syndecans and other proteoglycans in
convenient chemical handles for modifying them. These different contexts – and with different GAG arrangements
and other aspects of their research platform enable the be secreted from the cell to perform other functions. – and otherwise to explore their structures and functions.
systematic study of how proteoglycans’ structure affects With such complexity, it is no surprise that “Chemical editing of proteoglycan architecture”
their functions in health and disease. The scientists proteoglycans have versatile functions—they are present was co-authored by Timothy O’Leary, Meg Critcher,
demonstrated the effectiveness of their platform by using in virtually all tissues, including cartilage, collagen, bone, Tesia Stephenson, Xueyi Yang, Abdullah Hassan, Noah
it to make new discoveries about proteoglycans’ roles in skin, blood vessels, brain cells and mucosal surfaces. Bartfield, Richard Hawkins, and Mia Huang.
early cell development and in cancer cell spreading. They help steer processes such as cell maturation, cell Funding for the research was provided by the National
“We’re essentially unpacking the complexity of adhesion, cell migration, and neuronal synapse formation; Institutes of Health (R00HD090292, R35GM142462).
these molecules by constructing them in a modular way serve as receptors for protein signaling partners; and are
ourselves, and studying them in a tightly controlled even used by some viruses and bacteria to latch onto cells. Chemists Synthesize
environment,” says study senior author Mia Huang, But proteoglycans’ complexity also means that how they
Ph.D., associate professor in the Department of Molecular do what they do, and with what partners, remains largely Psychotropic Compound
Medicine at Scripps Research. undiscovered. Scientists aren’t even certain how many
A proteoglycan starts as just a protein – the so-called proteoglycans there are in human and other mammalian From Rainforest Tree
core protein – but this protein contains special sites where cells – although there are at least dozens.
any of a variety of sugar-related molecular chains called Huang and her team, including first authors Timothy Scripps Research scientists found the chemical
glycosaminoglycans (GAGs) can be linked. Within the O’Leary, Ph.D. and Meg Critcher, respectively a binds to opioid receptors in the brain and may have
cell where the protein originates, enzymes catalyze the postdoctoral researcher and doctoral candidate in the utility as an antidepressant or anti-anxiety drug.
attachment of GAGs to it, and this newborn proteoglycan Huang Lab during the study, constructed proteoglycan The bark of the Galbulimima belgraveana tree, found
normally is further decorated with clusters of sulfur and core proteins that are almost identical to known core only in remote rainforests of Papua New Guinea and
oxygen atoms called sulfates. The finished proteoglycan proteins, but contain special molecular handles enabling northern Australia, has long been used by indigenous
may be anchored into the cell membrane, its GAG chains the researchers to change the numbers and locations and
waving in the extracellular fluid like seagrass, or it may types of GAG chains that bind to them. This allows the Scripps Research on page 16

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