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Structural plasticity mediates distinct GAP-dependent GTP hydrolysis mechanisms in Rab33 and Rab5.

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Relation http://ir.cftri.com/13327/
http://dx.doi.org/10.1111/febs.14314
 
Title Structural plasticity mediates distinct GAP-dependent GTP
hydrolysis mechanisms in Rab33 and Rab5.
 
Creator Soneya, Majumdar
Abhishek, Acharya
Balaji, Prakash
 
Subject 03 Biochemistry & Molecular Biology
 
Description The classical GTP hydrolysis mechanism, as seen in Ras, employs a catalytic
glutamine 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-Glnmediated
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, which 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 allow structural plasticity,
or in other words, the choice of different catalytic mechanisms.
 
Date 2017
 
Type Article
PeerReviewed
 
Format pdf
 
Language en
 
Identifier http://ir.cftri.com/13327/1/The%20FEBS%20Journal%20284%20%282017%29%204358%E2%80%934375.pdf
Soneya, Majumdar and Abhishek, Acharya and Balaji, Prakash (2017) Structural plasticity mediates distinct GAP-dependent GTP hydrolysis mechanisms in Rab33 and Rab5. The FEBS journal, 284. pp. 4358-4375. ISSN 1742-464X