Allostery: Absence of a Change in Shape Does Not Imply that Allostery Is Not at Play

Tsai, Chung‐Jung; Sol, Antonio del; Nussinov, Ruth

doi:10.1016/j.jmb.2008.02.034

Cited by 417 publications

(460 citation statements)

References 56 publications

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“…Transdomain "cross-talk" between a catalytic center and a distal loop is an emerging theme by which single domains can transmit cellular signals (7,(53)(54)(55). In the single-domain protein interleukin-1β, point mutations that are distal to the receptor binding interface have no effect on stability, yet they have significant effects on the binding properties (55).…”

Section: Discussionmentioning

confidence: 99%

Allostery in the ferredoxin protein motif does not involve a conformational switch

Nechushtai

Lammert²,

Michaeli³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of protein function via cracking, or local unfolding and refolding of substructures, is becoming a widely recognized mechanism of functional control. Oftentimes, cracking events are localized to secondary and tertiary structure interactions between domains that control the optimal position for catalysis and/or the formation of protein complexes. Small changes in free energy associated with ligand binding, phosphorylation, etc., can tip the balance and provide a regulatory functional switch. However, understanding the factors controlling function in single-domain proteins is still a significant challenge to structural biologists. We investigated the functional landscape of a single-domain planttype ferredoxin protein and the effect of a distal loop on the electron-transfer center. We find the global stability and structure are minimally perturbed with mutation, whereas the functional properties are altered. Specifically, truncating the L1,2 loop does not lead to large-scale changes in the structure, determined via X-ray crystallography. Further, the overall thermal stability of the protein is only marginally perturbed by the mutation. However, even though the mutation is distal to the iron-sulfur cluster (∼20 Å), it leads to a significant change in the redox potential of the ironsulfur cluster (57 mV). Structure-based all-atom simulations indicate correlated dynamical changes between the surface-exposed loop and the iron-sulfur cluster-binding region. Our results suggest intrinsic communication channels within the ferredoxin fold, composed of many short-range interactions, lead to the propagation of long-range signals. Accordingly, protein interface interactions that involve L1,2 could potentially signal functional changes in distal regions, similar to what is observed in other allosteric systems.electron transfer | functional energy landscape | iron-sulfur proteins | protein folding O ver the last several decades, our understanding of protein function has evolved from a rather static perspective, where signaling and function have been understood through surface complementarity arguments, such as the "lock and key" paradigm (1, 2), to a more dynamic view where protein conformational fluctuations are inextricably linked to function (3). As our understanding of protein dynamics expands, we are revealing many mechanisms by which proteins exploit conformational fluctuations to perform cellular function. In multidomain proteins, relative repositioning of domains is often linked to their levels of activity. For example, large-scale domain rearrangements in the four-domain Src kinase (4) and C-terminal Src kinase (5, 6) lead to these proteins being in so-called "on" or "off" states, and functional regulation may be obtained by adjusting the balance between these conformations (7). In proteins such as adenylate kinase, domain rearrangements can be rate limiting during each round of catalysis (8), where the enzyme cycles between ligandcompetent and ligand-release conformations. Because the kinetics of these tra...

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Section: Discussionmentioning

confidence: 99%

Allostery in the ferredoxin protein motif does not involve a conformational switch

Nechushtai

Lammert²,

Michaeli³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In mechanical models of allostery signal transmission occurs through a pathway(s) in which alterations in bonding interactions propagate from the effector binding site to the site of functional change in a macromolecule. Recent studies indicate that allosteric signaling can also be entropically based (5,30,31). The effector-induced changes hydrogen-deuterium exchange in BirA indicate that this system provides another example of transmission of an allosteric response through alterations in protein fluctuations.…”

Section: Discussionmentioning

confidence: 99%

Allosteric Signaling in the Biotin Repressor Occurs via Local Folding Coupled to Global Dampening of Protein Dynamics

Laine

Streaker

Nabavi

et al. 2008

Journal of Molecular Biology

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SummaryThe biotin repressor is an allosterically regulated site-specific DNA binding protein. Binding of the small ligand, bio-5'-AMP, activates repressor dimerization, which is a prerequisite to DNA binding. Multiple disorder-to-order transitions, some of which are known to be important for the functional allosteric response, occur in the vicinity of the ligand binding site concomitant with effector binding to the repressor monomer. In this work the extent to which these local changes are coupled to additional changes in the structure/dynamics of the repressor was investigated using HydrogenDeuterium exchange coupled to Mass Spectrometry. Measurements were performed on the apoprotein and on complexes of the protein bound to four different effectors that elicit a range of thermodynamic responses in the repressor. Global exchange measurements indicate that binding of any effector to the intact protein is accompanied by protection from exchange. Mass spectrometric analysis of pepsin-cleavage products generated from the exchanged complexes reveals that the protection is distributed throughout the protein. Furthermore, the magnitude of the level of protection in each peptide from H-D exchange correlates with the magnitude of the functional allosteric response elicited by a ligand. These results indicate that local structural changes in the binding site that occur concomitant with effector binding nucleate global dampening of dynamics. Moreover, the magnitude of dampening of repressor dynamics tracks with magnitude of the functional response to effector binding.

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“…This classical view can be characterized by three main attributes: (i) only two states exist (e.g., "active" or "inactive"); (ii) the allosteric signal is relayed through a single well-defined pathway; and (iii) a conformational change occurs in the nonoverlapping site. A modern interpretation treats the native state as a conformational ensemble (rather than only two conformational states) whose preexisting population of conformations can be redistributed as a result of some allosteric perturbation that can be transmitted through multiple signaling pathways (3)(4)(5)(6). This "unified view" defines allostery in purely structural and thermodynamic terms (i.e., allostery can be controlled by entropy and/or enthalpy) and provides a quantitative framework for classifying allosteric mechanisms.…”

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confidence: 99%

Prepaying the entropic cost for allosteric regulation in KIX

Law¹,

Gagnon²,

Mapp

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The kinase-inducible domain interacting (KIX) domain of the CREB binding protein (CBP) is capable of simultaneously binding two intrinsically disordered transcription factors, such as the mixedlineage leukemia (MLL) and c-Myb peptides, at isolated interaction sites. In vitro, the affinity for binding c-Myb is approximately doubled when KIX is in complex with MLL, which suggests a positive cooperative binding mechanism, and the affinity for MLL is also slightly increased when KIX is first bound by c-Myb. Expanding the scope of recent NMR and computational studies, we explore the allosteric mechanism at a detailed molecular level that directly connects the microscopic structural dynamics to the macroscopic shift in binding affinities. To this end, we have performed molecular dynamics simulations of free KIX, KIX-c-Myb, MLL-KIX, and MLL-KIX-c-Myb using a topology-based Go-like model. Our results capture an increase in affinity for the peptide in the allosteric site when KIX is prebound by a complementary effector and both peptides follow an effector-independent folding-and-binding mechanism. More importantly, we discover that MLL binding lowers the entropic cost for c-Myb binding, and vice versa, by stabilizing the L 12 -G 2 loop and the C-terminal region of the α 3 helix on KIX. This work demonstrates the importance of entropy in allosteric signaling between promiscuous molecular recognition sites and can inform the rational design of small molecule stabilizers to target important regions of conformationally dynamic proteins.

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Allostery: Absence of a Change in Shape Does Not Imply that Allostery Is Not at Play

Cited by 417 publications

References 56 publications

Allostery in the ferredoxin protein motif does not involve a conformational switch

Allostery in the ferredoxin protein motif does not involve a conformational switch

Allosteric Signaling in the Biotin Repressor Occurs via Local Folding Coupled to Global Dampening of Protein Dynamics

Prepaying the entropic cost for allosteric regulation in KIX

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