Structural and Mechanistic Insights into Regulation of RGS17 and PLCepsilon

Description

<p>Recent advances in structural biology and biochemistry have
identified proteins downstream of G protein-coupled receptors (GPCRs) as
promising drug targets. These proteins are highly regulated to ensure proper
physiological responses from extracellular stimuli. Dysregulation of these
signaling enzymes can have detrimental consequences, including cardiovascular
disease and cancer. Understanding how these proteins are regulated from a
structural and biochemical standpoint can therefore be exploited to develop new
therapeutics.</p>

<p>In this work, the molecular mechanism of regulation of two
different proteins downstream of GPCRs is investigated. The first protein, Regulator of G Protein Signaling
17 (RGS17), is involved in numerous processes throughout the body, including
the development and progression of lung cancer.
This work presents the crystal structure of RGS17 bound to Ca²⁺. Ca²⁺ was found to bind to the same
site as the predicted Ga
binding surface and increases interactions between RGS17 and Ga_o. Therefore, Ca²⁺ positively
regulates RGS17, supporting a mechanism in which Ca²⁺ increases the
GTPase activating function of the RZ-family of RGS proteins to ultimately
downregulate Ca²⁺ signaling.</p>

<p>The second protein, phospholipase Ce (PLCe), has been implicated in
cardiac hypertrophy through its production of second messengers. This process is regulated by the small GTPase
Rap1A. This work presents insight into the
molecular mechanism of Rap1A-dependent activation of PLCe, in which four conserved,
hydrophobic residues on the surface of the RA2 domain of PLCe play an essential role. Furthermore, small angle X-ray scattering
studies show that binding of Rap1A induces conformational changes in PLCe, resulting in a more compact
activated complex. This supports a
mechanism in which Rap1A is an allosteric activator of PLCe, inducing conformational
changes in PLCe that increase lipid hydrolysis
by relieving autoinhibitory interactions and/or by promoting interactions with
the cell membrane.</p>

Links & Downloads

1. 10.25394/pgs.8411873.v1

Tags

Biochemistry

RGS17

PLCepsilon

SAXS

Calcium

Rap1A

Additional Fields

Identifer	oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/8411873
Date	15 August 2019
Creators	Monita Sieng (6901259)
Source Sets	Purdue University
Detected Language	English
Type	Text, Thesis
Rights	CC BY 4.0
Relation	https://figshare.com/articles/Structural_and_Mechanistic_Insights_into_Regulation_of_RGS17_and_PLCepsilon/8411873