Nancy B. Schwartz, Ph.D.
Defects in Proteoglycan Synthesis Associated with
Abnormal Skeletal and Brain Development
Research Summary
One
area of interest focuses on how the machinery for sulfation, a common
posttranslational modification of proteins, lipids and carbohydrates is
organized and controlled in higher organisms. The integrated pathway
for
sulfate uptake, activation and utilization encompasses multiple
components and
multiple intracellular compartments. At the center of this process is
the
bifunctional PAPS synthetase which synthesizes
phosphoadenosylphosulfate (PAPS)
from ATP and SO42- in a two-step process. We have discovered the PAPS
synthetase gene family, identified mutations in PAPS synthetase that
lead to
both human and animal chondrodystrophies and elucidated unique
enzymatic
properties, including channeling of the intermediate APS. Several
questions are
being addressed: 1) What features of the fused bifunctional PAPS
synthetase
account for the unique mechanistic properties, especially the
channeling
phenomena? Mutagenic analysis, biophysical and structural approaches
are being
employed; 2) What is the role of the multiple PAPS synthetase family
members
with respect to tissue- and developmental-specific expression? A
multi-faceted
approach is being used to quantitate each isoform, elucidate mechanisms
of
transcriptional regulation and determine the consequences of
manipulation of
isoform expression, include knockout and knockdown models; 3) Does PAPS
synthetase have a broader role in the overall uptake, activation and
utilization pathway? Potential advantageous interactions with
membrane-bound
and soluble components are being probed. These studies are aided by the
availability of a mutant model system with a sulfation defect that
results in
altered proteoglycan production and abnormal skeletal growth and
development.
Overall the long-term goal is to provide a model of the temporal and
topological organization of this critically important pathway, how it
is
regulated, and to correlate defects in the overall pathway with
abnormal growth
and development.
Selected Papers
Domowicz M, Mueller MM,
Novak TE, Schwartz LE
and Schwartz NB. (2003). Developmental expression of the HNK-1
carbohydrate
epitope on aggrecan during chondrogenesis. Devel. Dynamics, 226:42-50.
Domowicz M, Mangoura J, Schwartz NB.
(2003). Aggrecan regulates telencephalic neuronal aggregation in
Culture. Dev.
Brain Res, 143:207-216.
Schwartz NB and Domowicz, MS. (2004). Chondrodysplasias.
Encyclopedia of Endocrine Diseases, Elsevier Science, 1, 502-509.
Schwartz NB and Domowicz, MS. (2004). Proteoglycans in
Brain
Development. Glycoconjugate J. 21:327-339.
Schwartz NB and Domowicz, MS. (2004). Chondrodysplasias.
Encyclopedia of Endocrine Diseases, Elsevier Science, 1, 502-509.
Schwartz NB. (2005). PAPS and Sulfoconjugation, Human
Cystolic
Sulfotransferases. London:
Taylor and Francis, 43-57
Pirok E, Domowicz M,
Henry J, Wang Y, Santore
M, Mueller M and Schwartz NB. (2005). ARBP-I, A DNA/RNA binding
protein,
interacts with the chick aggrecan regulatory region. J Biol Chem
280:35606-35616.
Schwartz NB. Sulfation: The last steps in synthesis of
proteoglycans. Trends in Glycoscience and Glycotechnology, in press.
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