The Transition State of Coupled Folding and Binding for a Flexible β-Finger

Karlsson, O.; Celestine, N.; Engström, Åke; Jemth, Per

doi:10.1016/j.jmb.2012.01.042

Cited by 39 publications

(51 citation statements)

References 45 publications

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“…This suggests that electrostatics may be one of the key determinants for the fast associations that have been experimentally observed for some IDPs (26). We note that in general, k on values for IDPs and intrinsically disordered regions may not be larger than those of ordered proteins (18,19,26,27).…”

Section: Discussionmentioning

confidence: 71%

“…If the conformational changes occurred before binding, TMAO should affect the fast equilibrium and thus the association rate constant because TMAO selectively stabilizes more ordered structures. The lack of effect on k on also suggests that native interactions are formed late in the binding reaction (18,19). Thus, we propose that the two non-concentration-dependent phases we observe are related to steps occurring after initial binding (induced fit).…”

Section: Design and Validation Of Tryptophan Variants Of Ncbd Andmentioning

confidence: 65%

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Fast Association and Slow Transitions in the Interaction between Two Intrinsically Disordered Protein Domains

Dogan

Schmidt

et al. 2012

Journal of Biological Chemistry

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132

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Background: Intrinsically disordered proteins are common regulators of protein-protein interactions, but little is known about their mechanisms of interaction. Results: Two intrinsically disordered protein domains, from ACTR and CREB-binding protein, interact through rapid association and slow conformational changes. Conclusion: Electrostatics governs the fast association, but the overall reaction is multistep. Significance: The slow conformational search may be common among intrinsically disordered proteins with many binding partners.

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Section: Discussionmentioning

confidence: 71%

Section: Design and Validation Of Tryptophan Variants Of Ncbd Andmentioning

confidence: 65%

Fast Association and Slow Transitions in the Interaction between Two Intrinsically Disordered Protein Domains

Dogan

Schmidt

et al. 2012

Journal of Biological Chemistry

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132

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“…This is consistent with our proposal that the energy landscape of IDPs often has a certain degree of funneledness. Another feature, namely the low-barrier (or downhill) folding of N TAIL during its binding to XD, is also shared by a few other IDPs (12,65,90). Our previous simulations of coupled folding and binding of two IDPs, namely proteinase inhibitor IA3 (10) and histone chaperone Chz1 (11), unveiled that their induced folding is also downhilllike (the energy barriers are less than 1k B T), although we did not emphasize this point in those studies.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, an increasing number of studies emphasized a relationship between MG and downhill folding (67,91,92), between downhill folding and IDP (12,65,90), and finally between MG and IDP (4, 26, 88, 89, 93, 94). From the energy landscape perspective, the MG state is between the unfolded state at the top of the funnel and the folded state at the bottom of the funnel (78).…”

Section: Discussionmentioning

confidence: 99%

Multiscaled exploration of coupled folding and binding of an intrinsically disordered molecular recognition element in measles virus nucleoprotein

Wang

Chu

Longhi

et al. 2013

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

108

119

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Numerous relatively short regions within intrinsically disordered proteins (IDPs) serve as molecular recognition elements (MoREs). They fold into ordered structures upon binding to their partner molecules. Currently, there is still a lack of in-depth understanding of how coupled binding and folding occurs in MoREs. Here, we quantified the unbound ensembles of the α-MoRE within the intrinsically disordered C-terminal domain of the measles virus nucleoprotein. We developed a multiscaled approach by combining a physics-based and an atomic hybrid model to decipher the mechanism by which the α-MoRE interacts with the X domain of the measles virus phosphoprotein. Our multiscaled approach led to remarkable qualitative and quantitative agreements between the theoretical predictions and experimental results (e.g., chemical shifts). We found that the free α-MoRE rapidly interconverts between multiple discrete partially helical conformations and the unfolded state, in accordance with the experimental observations. We quantified the underlying global folding-binding landscape. This leads to a synergistic mechanism in which the recognition event proceeds via (minor) conformational selection, followed by (major) induced folding. We also provided evidence that the α-MoRE is a compact molten globule-like IDP and behaves as a downhill folder in the induced folding process. We further provided a theoretical explanation for the inherent connections between "downhill folding," "molten globule," and "intrinsic disorder" in IDP-related systems. Particularly, we proposed that binding and unbinding of IDPs proceed in a stepwise way through a "kinetic divide-and-conquer" strategy that confers them high specificity without high affinity. multiscale simulation | hybrid structure-based model | free-energy surface | flexible binding | flexible recognition I ntrinsically disordered proteins (IDPs) are a newly recognized class of naturally abundant, functional proteins that are unable to fold into a well-defined secondary or tertiary structure under physiological conditions of pH and salinity in the absence of a partner (1-3). IDPs perform a wide spectrum of biological functions, often related to molecular recognition, signal transduction, and cell regulation (4). In contrast, canonical proteins with ordered structure mainly carry out their functions in catalysis and membrane transport (5). The functional repertoire of ordered proteins and that of IDPs are complementary to each other (2, 4). Earlier bioinformatics studies predicted that more than 50% of eukaryotic proteins have long disordered regions (1, 6), and the proportion further increases up to 70% in signaling proteins (7). Due to their ubiquitous occurrence in the living world and close relationship with human diseases, IDPs have in recent years become a hot topic in protein science (3,8). One of the most interesting characteristics of IDPs is that they often undergo disorder-to-order transitions upon binding to their partner(s), such as proteins or DNA (9-14), even though some IDP-p...

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“…1b). In general, only very few functional studies of b-finger interaction to the PDZ domains have been performed 27,47,48 . Thus, to investigate the role of the H-bonds in this non-canonical interaction we evaluated our A-to-E mutants of PSD-95-PDZ2 and ZO-1-PDZ1 for binding to the b-finger motif of nNOS.…”

Section: Semisynthesis Of Pdz Domainsmentioning

confidence: 99%

Probing backbone hydrogen bonding in PDZ/ligand interactions by protein amide-to-ester mutations

Pedersen

Anker

et al. 2014

Nat Commun

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PDZ domains are scaffolding modules in protein-protein interactions that mediate numerous physiological functions by interacting canonically with the C-terminus or non-canonically with an internal motif of protein ligands. A conserved carboxylate-binding site in the PDZ domain facilitates binding via backbone hydrogen bonds; however, little is known about the role of these hydrogen bonds due to experimental challenges with backbone mutations. Here we address this interaction by generating semisynthetic PDZ domains containing backbone amide-to-ester mutations and evaluating the importance of individual hydrogen bonds for ligand binding. We observe substantial and differential effects upon amide-to-ester mutation in PDZ2 of postsynaptic density protein 95 and other PDZ domains, suggesting that hydrogen bonding at the carboxylate-binding site contributes to both affinity and selectivity. In particular, the hydrogen-bonding pattern is surprisingly different between the non-canonical and canonical interaction. Our data provide a detailed understanding of the role of hydrogen bonds in protein-protein interactions.

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The Transition State of Coupled Folding and Binding for a Flexible β-Finger

Cited by 39 publications

References 45 publications

Fast Association and Slow Transitions in the Interaction between Two Intrinsically Disordered Protein Domains

Fast Association and Slow Transitions in the Interaction between Two Intrinsically Disordered Protein Domains

Multiscaled exploration of coupled folding and binding of an intrinsically disordered molecular recognition element in measles virus nucleoprotein

Probing backbone hydrogen bonding in PDZ/ligand interactions by protein amide-to-ester mutations

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