The role of dynamics in allosteric regulation
Dorothee Kern
and Erik RP Zuiderweg
y
The biomolecular conformational changes often associated with
allostery are, by definition, dynamic processes. Recent
publications have disclosed the role of pre-existing equilibria
of conformational substates in this process. In addition, the
role of dynamics as an entropic carrier of free energy of
allostery has been investigated. Recent work thus shows that
dynamics is pivotal to allostery, and that it constitutes much
more than just the move from the ‘T’-state to the ‘R’-state.
Emerging computational studies have described the actual
pathways of allosteric change.
Addresses
Department of Biochemistry, Brandeis University, 415 South Street,
Waltham, MA 02454-9110, USA
e-mail: dkern@brandeis.edu
y
Biophysics Research Division and Departments of Biological Chemistry
and Chemistry, The University of Michigan, 930 North University Avenue,
Ann Arbor, MI 48109-1055, USA
e-mail: zuiderwe@umich.edu
Current Opinion in Structural Biology 2003, 13:748–757
This review comes from a themed issue on
Catalysis and regulation
Edited by Bauke W Dijkstra and Rowena G Matthews
0959-440X/$ – see front matter
ß 2003 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.sbi.2003.10.008
Abbreviations
KNF Koshland, Nemethy and Filmer
MD molecular dynamics
MWC Monod, Wyman and Changeux
PDB Protein Data Bank
rms root mean square
Introduction
Dynamic processes in biomolecules cover a large timescale
regime, including very fast fluctuations of individual atoms
on the picosecond timescale, loop and domain motions on
the nanosecond timescale, conformational rearrangements
on the millisecond timescale and breathing modes on a
timescale slower than seconds. Several excellent reviews
summarize the functional role of dynamics in catalysis
[1,2]. Here, we review the role of dynamics in allostery.
Allostery (‘allo-steric ¼ other-space’) means that action in
one part of the molecule causes an effect at another site.
Allosteric processes are closely associated with ligand-
induced conformational changes that propagate between
the allosterically coupled binding sites [3]. The allosteric
molecule thus changes its coordinates as a function of time,
which constitutes dynamics. Hence, dynamics and allo-
steric processes are almost tautologically linked. In addi-
tion, changes in the dynamic properties of the different
conformations of the allosteric protein may contribute to
the free energy of allosteric coupling through entropic
effects [4]. This review focuses on the different types of
dynamics of allosteric proteins. Purists may associate only
quasi-harmonic motions on the shortest timescales with
the word dynamics. In this review, however, we will
consider all motions — quasi-harmonic, diffusive rearran-
gements or fluctuations in populations over an ensemble of
subconformations — as dynamics. The review ignores the
role of allosteric proteins in systemic dynamic processes,
such as the dynamic changes of gene expression and
neuron proliferation.
It is often stated that allosteric systems are oligomeric and
symmetric (e.g. [5]); for this review, we want to take a
broader point of view. We define here as allosteric those
systems in which the binding of one ligand affects the
affinity of another ligand (Figure 1). This includes, in
addition to the classical homotropic oligomeric systems
such as hemoglobin and aspartate transcarbamylase, het-
erotropic monomeric systems such as Hsp70 chaperones,
whereby allosteric coupling exists between ATP binding
in one domain and protein substrate binding in another
domain [6], and single-domain proteins, whereby phos-
phorylation at one site affects the structure of the protein
in a remote area [7,8
]. Our definition also includes those
proteins for which at least one of the ligands is a biological
macromolecule; good examples are the Trp- and RNA-
binding attenuation protein repressor, for which trypto-
phan binding affects RNA binding at a remote site [9
],
and processes such as ligand-coupled oligomerization
[10,11].
We want to mention a few developments that have made
many of the exciting recent discoveries in allosteric
dynamics feasible. Improvements in mutagenesis and
site-specific labeling techniques extended the applicabil-
ity of fluorescence lifetime methods beyond naturally
available tryptophan residues [12]. Ultrafast laser tech-
nologies can resolve many time steps in dynamic pro-
cesses [13]. The measurement of site-resolved quasi-
harmonic dynamics on the picosecond to nanosecond
timescale by NMR relaxation methods is feasible for
both protein backbone and protein sidechains [14–16].
Fluctuations between conformational substates on the
millisecond to microsecond timescale can now be mea-
sured quantitatively and site resolved by NMR as well
[17]. Importantly, NMR dynamic measurements can now
be combined with TROSY detection methods [18], which
extends its application to larger systems, such as a 91 kDa
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