Adaptability of protein structures to enable functional interactions and evolutionary implications

Haliloğlu, Türkan; Bahar, İvet

doi:10.1016/j.sbi.2015.07.007

Cited by 110 publications

(93 citation statements)

References 70 publications

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“…Because these are the most important directions of structural variations, the two PCs represent a convenient and efficient set of coordinates upon which to construct energy landscapes (29,30). Analogous to the x, y, and z directions, the PC directions are orthogonal and can be considered to form a multidimensional landscape, and the structures can be projected onto this space.…”

Section: Cadherin Energy Landscape and Transition Pathway For The Intmentioning

confidence: 99%

Molecular determinants of cadherin ideal bond formation: Conformation-dependent unbinding on a multidimensional landscape

Manibog

Sankar

Kim

et al. 2016

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

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Classical cadherin cell-cell adhesion proteins are essential for the formation and maintenance of tissue structures; their primary function is to physically couple neighboring cells and withstand mechanical force. Cadherins from opposing cells bind in two distinct trans conformations: strand-swap dimers and X-dimers. As cadherins convert between these conformations, they form ideal bonds (i.e., adhesive interactions that are insensitive to force). However, the biophysical mechanism for ideal bond formation is unknown. Here, we integrate single-molecule force measurements with coarsegrained and atomistic simulations to resolve the mechanistic basis for cadherin ideal bond formation. Using simulations, we predict the energy landscape for cadherin adhesion, the transition pathways for interconversion between X-dimers and strand-swap dimers, and the cadherin structures that form ideal bonds. Based on these predictions, we engineer cadherin mutants that promote or inhibit ideal bond formation and measure their force-dependent kinetics using single-molecule force-clamp measurements with an atomic force microscope. Our data establish that cadherins adopt an intermediate conformation as they shuttle between X-dimers and strandswap dimers; pulling on this conformation induces a torsional motion perpendicular to the pulling direction that unbinds the proteins and forms force-independent ideal bonds. Torsional motion is blocked when cadherins associate laterally in a cis orientation, suggesting that ideal bonds may play a role in mechanically regulating cadherin clustering on cell surfaces.T he formation and maintenance of multicellular structures rely upon specific and robust intercellular adhesion (1). Cell-cell adhesion proteins, such as classical cadherins, are crucial in these processes (2-4). Cadherins are Ca 2+ -dependent transmembrane proteins that mediate the integrity of all soft tissues. One of their principal functions is to bind cells and dampen mechanical perturbations; however, the biophysical mechanism by which cadherins tune adhesion is not understood. Here, we combine predictive simulations with quantitative single-molecule force-clamp measurements to show that E-cadherin (Ecad), a prototypical classical cadherin, dampens the effect of tugging forces by switching conformations and unbinding along a strongly preferred pathway on a multidimensional landscape.Cadherin adhesive function resides in their ectodomain that is comprised of five extracellular (EC) domains arranged in tandem (5-9). Structural studies (10-15) and single-molecule fluorescence measurements (16) show that opposing ectodomains bind in two distinct trans conformations: strand-swap dimers (S-dimers) and X-dimers. S-dimers, which have a higher binding affinity, are formed by the exchange of a conserved tryptophan at position 2 (W2) between binding partners (10, 13, 17-19). In contrast, low-affinity X-dimers are formed by extensive surface interactions around the linker region that connects the two outermost domains (EC1-EC2) (11,12,(14)(15)...

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Section: Cadherin Energy Landscape and Transition Pathway For The Intmentioning

confidence: 99%

Molecular determinants of cadherin ideal bond formation: Conformation-dependent unbinding on a multidimensional landscape

Manibog

Sankar

Kim

et al. 2016

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

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“…7b). Note that these motions are readily accessible via thermal fluctuations, and it is plausible that the human and mouse IFNAR1 adapt to different experimental conditions, functional states and/or sequence variations by simply reconfiguring along these soft directions of global movements (for a review see (Haliloglu and Bahar, 2015)).…”

Section: Resultsmentioning

confidence: 99%

Dynamic Modulation of Binding Affinity as a Mechanism for Regulating Interferon Signaling

Sharma

General

et al. 2017

Journal of Molecular Biology

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How structural dynamics affects cytokine signaling is under debate. Here, we investigated the dynamics of the type I interferon (IFN) receptor, IFNAR1, and its effect on signaling upon binding IFN and IFNAR2 using a combination of structure-based mechanistic studies, in situ binding and gene induction assays. Our study reveals that IFNAR1 flexibility modulates ligand-binding affinity, which, in turn, regulates biological signaling. We identified the hinge sites and key interactions implicated in IFNAR1 inter-subdomain (SD1-SD4) movements. We showed that the predicted cooperative movements are essential to accommodate intermolecular interactions. Engineered disulfide bridges, computationally predicted to interfere with IFNAR1 dynamics, were experimentally confirmed. Notably, introducing disulfide bonds between subdomains SD2 and SD3 modulated IFN binding and activity in accordance with the relative attenuation of cooperative movements with varying distance from the hinge center; whereas locking the SD3-SD4 interface flexibility in favor of an extended conformer increased activity.

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“…Collective global modes of motions are evolutionary conserved structural motions essential for a protein's functional activity. In that respect, the present analysis is based on the premise that somatic missense mutations likely appear as global perturbations to the protein's intrinsic dynamics …”

Section: Introductionmentioning

confidence: 99%

Protein dynamics analysis reveals that missense mutations in cancer‐related genes appear frequently on hinge‐neighboring residues

2019

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Missense mutations have various effects on protein structures, also leading to distorted protein dynamics that plausibly affects the function. We hypothesized that missense mutations in cancer‐related genes selectively target hinge‐neighboring residues that orchestrate collective structural dynamics. To test our hypothesis, we selected 69 cancer‐related genes from the Cancer Gene Census database and their representative protein structures from the Protein Data Bank. We first identified the hinge residues in two global modes of motion by applying the Gaussian Network Model. We then showed that missense mutations are significantly enriched on hinge‐neighboring residues in oncogenes and tumor suppressor genes. We observed that several oncogenes (eg, MAP2K1, PTPN11, and KRAS) and tumor suppressor genes (eg, EZH2, CDKN2C, and RHOA) strongly exhibit this phenomenon. This study highlights and rationalizes the functional importance of missense mutations on hinge‐neighboring residues in cancer.

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Adaptability of protein structures to enable functional interactions and evolutionary implications

Cited by 110 publications

References 70 publications

Molecular determinants of cadherin ideal bond formation: Conformation-dependent unbinding on a multidimensional landscape

Molecular determinants of cadherin ideal bond formation: Conformation-dependent unbinding on a multidimensional landscape

Dynamic Modulation of Binding Affinity as a Mechanism for Regulating Interferon Signaling

Protein dynamics analysis reveals that missense mutations in cancer‐related genes appear frequently on hinge‐neighboring residues

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