Structural Plasticity mediates distinct GAP-dependent GTP hydrolysis mechanisms in Rab33 and Rab5.
FEBS J. 2017 Nov 02;:
Authors: Majumdar S, Acharya A, Prakash B
Abstract
The classical GTP hydrolysis mechanism, as seen in Ras, employs a catalytic Gln, provided in-cis by the GTPase, and an Arginine supplied in-trans by a GTPase Activating Protein (GAP). The key idea emergent from a large body of research on small GTPases is that GTPases employ a variety of different hydrolysis mechanisms; evidently, these variations permit diverse rates of GTPase inactivation, crucial for temporal regulation of different biological processes. Recently, we unified these variations and argued that a steric clash between active site residues (corresponding to positions 12 and 61 of Ras) governs whether a GTPase utilizes the cis-Gln or the trans-Gln (from the GAP) for catalysis. As the cis-Gln encounters a steric clash, the Rab GTPases employ the so-called dual finger mechanism where the interacting GAP supplies a trans-Gln for catalysis. Using experimental and computational methods, we demonstrate how the cis-Gln of Rab33 overcomes the steric clash when it is stabilized by a residue in the vicinity. In effect, this demonstrates how both cis-Gln and trans-Gln mediated mechanisms could operate in the same GTPase in different contexts, i.e. depending on the GAP that regulates its action. Interestingly, in the case of Rab5, that possesses a higher intrinsic GTP hydrolysis rate, a similar stabilization of the cis-Gln appears to overcome the steric clash. Taken together with the mechanisms seen for Rab1, it is evident that the observed variations in Rab and their GAP partners allows structural plasticity in other words, the choice of different catalytic mechanisms. This article is protected by copyright. All rights reserved.
PMID: 29095572 [PubMed - as supplied by publisher]
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