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A Functional Loop Spanning Distant Domains of Glutaminyl-tRNA Synthetase Also Stabilizes a Molten Globule State

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Title A Functional Loop Spanning Distant Domains of Glutaminyl-tRNA
Synthetase Also Stabilizes a Molten Globule State
 
Creator Saha, Rajesh
Dasgupta, Saumya
Banerjee, Rajat
Mitra-Bhattacharyya, Anusree
Söll, Dieter
Basu, Gautam
Roy, Siddhartha
 
Subject Structural Biology & Bioinformatics
 
Description Molten globule and other disordered states of
proteins are now known to play important roles in many
cellular processes. From equilibrium unfolding studies of two
paralogous proteins and their variants, glutaminyl-tRNA
synthetase (GlnRS) and two of its variants [glutamyl-tRNA
synthetase (GluRS) and its isolated domains, and a GluRS−
GlnRS chimera], we demonstrate that only GlnRS forms a
molten globule-like intermediate at low urea concentrations.
We demonstrated that a loop in the GlnRS C-terminal
anticodon binding domain that promotes communication with
the N-terminal domain and indirectly modulates amino acid binding is also responsible for stabilization of the molten globule
state. This loop was inserted into GluRS in the eukaryotic branch after the archaea−eukarya split, right around the time when
GlnRS evolved. Because of the structural and functional importance of the loop, it is proposed that the insertion of the loop into
a putative ancestral GluRS in eukaryotes produced a catalytically active molten globule state. Because of their enhanced dynamic
nature, catalytically active molten globules are likely to possess broad substrate specificity. It is further proposed that the putative
broader substrate specificity allowed the catalytically active molten globule to accept glutamine in addition to glutamic acid,
leading to the evolution of GlnRS.
Many functional proteins fold into a well-defined threedimensional
structure. However, it is now clear that not
all proteins fold into a uniquely defined native state
conformation. Many are intrinsically unfolded, while others
can be partially folded or present in a molten globule-like
structure in which the fold is compact but the internal mobility
is significantly enhanced.1 The molten globule class of compact
states is ubiquitous in nature, and in many cases, they are
produced under mildly denaturing conditions.2 However, for
many proteins, a molten globule state has not yet been detected
under several denaturing conditions, indicating that they are
energetically far removed from the native state. The
physicochemical properties that stabilize a molten globule
state with respect to the native state have not been fully
elucidated, except in a few cases. The most important insight
has come from pairs of paralogs in which one protein forms the
molten globule state under mild denaturing conditions and the
other does not.3 A classic example is that of the lysozyme−
lactalbumin pair. It has been concluded that non-native
interactions of a small part of bovine α-lactalbumin play a
crucial role in the stabilization of the molten globule state.4 It is
not known whether non-native contacts of a small region in a
protein play important roles in the stabilization of the molten
globule state of other proteins as well. If this
 
Publisher American Chemical Society
 
Date 2012
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1493/1/BIOCHEMISTRY__51(_22)_4429%2D4437;2012[4].pdf
Saha, Rajesh and Dasgupta, Saumya and Banerjee, Rajat and Mitra-Bhattacharyya, Anusree and Söll, Dieter and Basu, Gautam and Roy, Siddhartha (2012) A Functional Loop Spanning Distant Domains of Glutaminyl-tRNA Synthetase Also Stabilizes a Molten Globule State. Biochemistry, 51 (22). pp. 4429-4437.
 
Relation http://dx.doi.org/10.1021/bi300221t |
http://www.eprints.iicb.res.in/1493/