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2016 ; 111
(5
): 902-8
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Biased Allostery
#MMPMID27602718
Edelstein SJ
; Changeux JP
Biophys J
2016[Sep]; 111
(5
): 902-8
PMID27602718
show ga
G-protein-coupled receptors (GPCRs) constitute a large group of integral membrane
proteins that transduce extracellular signals from a wide range of agonists into
targeted intracellular responses. Although the responses can vary depending on
the category of G-proteins activated by a particular receptor, responses were
also found to be triggered by interactions of the receptor with ?-arrestins. It
was subsequently discovered that for the same receptor molecule (e.g., the
?-adrenergic receptor), some agonists have a propensity to specifically favor
responses by G-proteins, others by ?-arrestins, as has now been extensively
studied. This feature of the GPCR system is known as biased agonism and is
subject to various interpretations, including agonist-induced conformational
change versus selective stabilization of preexisting active conformations. Here,
we explore a complete allosteric framework for biased agonism based on
alternative preexisting conformations that bind more strongly, but
nonexclusively, either G-proteins or ?-arrestins. The framework incorporates
reciprocal effects among all interacting molecules. As a result, G-proteins and
?-arrestins are in steric competition for binding to the cytoplasmic surface of
either the G-protein-favoring or ?-arrestin-favoring GPCR conformation. Moreover,
through linkage relations, the strength of the interactions of G-proteins or
?-arrestins with the corresponding active conformation potentiates the apparent
affinity for the agonist, effectively equating these two proteins to allosteric
modulators. The balance between response alternatives can also be influenced by
the physiological concentrations of either G-proteins or ?-arrestins, as well as
by phosphorylation or interactions with positive or negative allosteric
modulators. The nature of the interactions in the simulations presented suggests
novel experimental tests to distinguish more fully among alternative mechanisms.
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