posted on 2024-03-15, 19:06authored byPrajakta Badve, Katlyn K. Meier
Progesterone receptor membrane component 1 (PGRMC1) binds
heme
via a surface-exposed site and displays some structural resemblance
to cytochrome b5 despite their different functions. In the case of
PGRMC1, it is the protein interaction with drug-metabolizing cytochrome
P450s and the epidermal growth factor receptor that has garnered the
most attention. These interactions are thought to result in a compromised
ability to metabolize common chemotherapy agents and to enhance cancer
cell proliferation. X-ray crystallography and immunoprecipitation
data have suggested that heme-mediated PGRMC1 dimers are important
for facilitating these interactions. However, more recent studies
have called into question the requirement of heme binding for PGRMC1
dimerization. Our study employs spectroscopic and computational methods
to probe and define heme binding and its impact on PGRMC1 dimerization.
Fluorescence, electron paramagnetic resonance and circular dichroism
spectroscopies confirm heme binding to apo-PGRMC1 and were used to
demonstrate the stabilizing effect of heme on the wild-type protein.
We also utilized variants (C129S and Y113F) to precisely define the
contributions of disulfide bonds and direct heme coordination to PGRMC1
dimerization. Understanding the key factors involved in these processes
has important implications for downstream protein–protein interactions
that may influence the metabolism of chemotherapeutic agents. This
work opens avenues for deeper exploration into the physiological significance
of the truncated-PGRMC1 model and developing design principles for
potential therapeutics to target PGRMC1 dimerization and downstream
interactions.