Interconversion between two unrelated protein folds in the lymphotactin native state

Tuinstra, Robbyn L.; Peterson, Francis C.; Kutlesa, Snjezana; Elgin, Emine Sonay; Kron, Michael; Volkman, Brian F.

doi:10.1073/pnas.0709518105

Cited by 261 publications

(441 citation statements)

References 39 publications

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“…Thus, instead of a single funnel, the energy landscape of such a protein has multiple basins of attraction [177,178]. In some cases, these alternative structures freely interconvert during the lifetime of the protein as for the cytokine lymphotactin [179] and the cell cycle control protein Mad2 [180]. Sometimes it takes an additional factor to stabilize an alternative structure, such as a change in the solvent conditions or a binding event (e.g.…”

Section: Multi-basin Folding Landscapes Allostery and Conformationalmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

219

207

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The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence-structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by 'hidden' conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution.

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Section: Multi-basin Folding Landscapes Allostery and Conformationalmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

219

207

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“…Classic examples of major conformational changes include influenza virus hemagglutinin upon interaction with the host cell (24), serpins upon proteolysis of a loop (25), and prion proteins that change from a mainly ␣-helical benign form (PrP C ) to an infectious state (PrP Sc ) with increased ␤-sheet content (26). Another recent example is the chemokine lymphotactin, which has 2 populated conformational states under physiologic conditions: the canonical chemokine fold (3-stranded ␤-sheet and C-terminal ␣-helix) in equilibrium with an all ␤-sheet dimer (27). Each conformation has a different binding function.…”

Section: Discussionmentioning

confidence: 99%

“…If a fold switch occurs in nature, sequences rapidly diverge thereafter. Lymphotactin and the Cro transcription factors seem to be 2 natural proteins that have been ''caught in the act,'' however (27,28).…”

Section: Discussionmentioning

confidence: 99%

A minimal sequence code for switching protein structure and function

Alexander

He²,

Chen³

et al. 2009

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

232

330

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We present here a structural and mechanistic description of how a protein changes its fold and function, mutation by mutation. Our approach was to create 2 proteins that (i) are stably folded into 2 different folds, (ii) have 2 different functions, and (iii) are very similar in sequence. In this simplified sequence space we explore the mutational path from one fold to another. We show that an IgG-binding, 4␤؉␣ fold can be transformed into an albumin-binding, 3-␣ fold via a mutational pathway in which neither function nor native structure is completely lost. The stabilities of all mutants along the pathway are evaluated, key high-resolution structures are determined by NMR, and an explanation of the switching mechanism is provided. We show that the conformational switch from 4␤؉␣ to 3-␣ structure can occur via a single amino acid substitution. On one side of the switch point, the 4␤؉␣ fold is >90% populated (pH 7.2, 20°C). A single mutation switches the conformation to the 3-␣ fold, which is >90% populated (pH 7.2, 20°C). We further show that a bifunctional protein exists at the switch point with affinity for both IgG and albumin.evolution ͉ NMR ͉ protein design ͉ protein folding

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“…77,78 This is consistent with the hypothesis that such bistable structures may function as evolutionary bridges between proteins carrying out different functions, supported by recent experimental and theoretical work. [79][80][81][82] In addition, several natural examples exist of proteins that populate different native states in the presence of different binding partners [83][84][85] and are not intrinsically disordered, indicating that this is not a property unique to IDPs. Nonetheless, it is likely to be easier for nature to design IDPs to bind in different structures, because of the larger contribution made by the binding interface to the overall stability.…”

Section: B Binding Transition Pathsmentioning

confidence: 99%

Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model

Knott

Best

2014

The Journal of Chemical Physics

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Many proteins undergo a conformational transition upon binding to their cognate binding partner, with intrinsically disordered proteins (IDPs) providing an extreme example in which a folding transition occurs. However, it is often not clear whether this occurs via an "induced fit" or "conformational selection" mechanism, or via some intermediate scenario. In the first case, transient encounters with the binding partner favour transitions to the bound structure before the two proteins dissociate, while in the second the bound structure must be selected from a subset of unbound structures which are in the correct state for binding, because transient encounters of the incorrect conformation with the binding partner are most likely to result in dissociation. A particularly interesting situation involves those intrinsically disordered proteins which can bind to different binding partners in different conformations. We have devised a multi-state coarse-grained simulation model which is able to capture the binding of IDPs in alternate conformations, and by applying it to the binding of nuclear coactivator binding domain (NCBD) to either ACTR or IRF-3 we are able to determine the binding mechanism. By all measures, the binding of NCBD to either binding partner appears to occur via an induced fit mechanism. Nonetheless, we also show how a scenario closer to conformational selection could arise by choosing an alternative non-binding structure for NCBD. © 2014 AIP Publishing LLC.

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Interconversion between two unrelated protein folds in the lymphotactin native state

Cited by 261 publications

References 39 publications

Biophysics of protein evolution and evolutionary protein biophysics

Biophysics of protein evolution and evolutionary protein biophysics

A minimal sequence code for switching protein structure and function

Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model

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