Structural motifs in the RGS RZ subfamily combine to attenuate interactions with Gα subunits
- The Department of Human Biology, Faculty of Natural Science, University of Haifa, Haifa, 3498838 (Israel)
Highlights: • RGS RZ subfamily specificity is set by four family-specific structural motifs. • These motifs are predicted to attenuate interactions with Gα subunits. • Insertion of these motifs into a high-activity RGS domain impaired its activity. • The motifs combine to affect activity in a non-additive manner. Regulators of G-protein Signaling (RGS) proteins inactivate heterotrimeric G proteins, thereby setting the duration of active signaling. In particular, the RGS RZ subfamily, which consists of RGS17, RGS19, and RGS20, mediates numerous physiological functions and human pathologies – mostly by functioning as GTPase Activating Proteins (GAPs) towards the Gα{sub i} subfamily. Yet, which RZ subfamily members mediate particular functions and how their GAP activity and specificity are governed at the amino acid level is not well understood. Here, we show that all RZ subfamily members have similar and relatively low GAP activity towards Gα{sub o}. We characterized four RZ-specific structural motifs that mediate this low activity, and suggest they perturb optimal interactions with the Gα subunit. Indeed, inserting these RZ-specific motifs into the representative high-activity RGS16 impaired GAP activity in a non-additive manner. Our results provide residue-level insights into the specificity determinants of the RZ subfamily, and enable to study their interactions in signaling cascades by using redesigned mutants such as those presented in this work.
- OSTI ID:
- 23103608
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 503, Issue 4; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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