Akademik Veri Yönetim Sistemi
ERNEST 8th and Final Meeting GPCR Structure and Function: The Present and perspectives for the future, Heraklion, Yunanistan, 3 - 07 Mayıs 2023, ss.78
Parkin-associated
endothelin-like receptor (Pael-R), commonly known as GPR37, is a brain-enriched
orphan GPCR. GPR37 has been linked to various neurological and
neurodegenerative illnesses despite its unknown physiological role.GPR37 is a
substrate for E3 parkin, a protein-ubiquitin ligase involved in the breakdown
and removal of aggregated proteins. GPR37 accumulates toxically when parkin
function is lost, such as in autosomal recessive juvenile parkinsonism. Similar
to this, GPR37 aggregates have been found in the Lewy bodies of Parkinson's
disease (PD) patients, indicating that they may be involved in the pathology of
PD. This merits investigating the physiological function of GPR37, with an
emphasis on its interaction with various neurotransmitter systems.
It has
been shown that the formation of homodimers and heterodimers by GPCRs is
important for the allosteric modulation of GPCR activity and pharmacology. Recent evidence suggests that GPR37 inhibits adenosine A2A
receptor (A2AR) cell surface expression and function by oligomerizing with A2AR
in the striatum (1). Furthermore, A2A receptor antagonist-mediated tremor
suppression was found to be impaired in GPR37 knockout mice (2). In this study,
we used a template-based molecular modeling approach based on known homodimer
crystal and cryo-EM structures to simulate the A2AR and GPR37 heterodimer
structure (3-7). Our proposed GPR37-A2AR heterodimer structures include two
possible interfaces, one with the transmembrane (TM) domains TM1, TM2, and H8,
and the other with the transmembrane (TM) domains TM4 and TM4. In the future,
our heterodimer models will be refined using molecular dynamics simulations in
a lipid bilayer, allowing us to construct additional
studies for model validation, such as mutagenesis and peptide-interference
assays.
Acknowledgments:
References:
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