Regulated unfolding: a basic principle of intraprotein signaling in modular proteins

Schultz, Joachim E.; Natarajan, Janani

doi:10.1016/j.tibs.2013.08.005

Cited by 45 publications

(52 citation statements)

References 60 publications

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“…For linear domain arrangements, changes in hydrophobic packing and helix orientations can be effectively communicated through the connecting coiled coils. At the extreme, these structural changes could involve near unfolding of the respective modules, relieving the influence of one domain over the other (4,7). Altering output domain stability could impact enzymatic function or the ability to engage partners.…”

Section: Resultsmentioning

confidence: 99%

“…These ideas have been largely supported by computational studies (2), although direct measurements also correlate dynamics with activity (1)(2)(3)(4). Nonetheless, we are only beginning to address the link between conformational heterogeneity and signal propagation in complex proteins.…”

mentioning

confidence: 94%

“…chemotaxis | transmembrane signaling receptor | allostery | dynamics | adaptation T he ability of localized dynamics to modulate the function of transmembrane receptors is an emerging theme in signal transduction (1)(2)(3)(4). These ideas have been largely supported by computational studies (2), although direct measurements also correlate dynamics with activity (1)(2)(3)(4).…”

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confidence: 99%

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Bacterial chemoreceptor dynamics correlate with activity state and are coupled over long distances

Samanta

Borbat

Dzikovski

et al. 2015

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

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Dynamics are hypothesized to play an important role in the transmission of signals across membranes by receptors. Bacterial chemoreceptors are long helical proteins that consist of a periplasmic ligand-binding domain; a transmembrane region; a cytoplasmic HAMP (histidine kinase, adenylyl cyclases, methyl-accepting chemotaxis proteins, and phosphatases) domain; and a kinase-control module (KCM). The KCM is further composed of adaptation, hinge, and protein interaction regions (PIRs), the latter of which binds the histidine kinase CheA and adaptor CheW. Fusions of the Escherichia coli aspartate receptor KCM to HAMP domains of defined structure (H1-Tar vs. H1-2-Tar) give opposite responses in phosphotransfer and cellular assays, despite similar binding to CheA and CheW. Pulsed dipolar ESR spectroscopy (PDS) of these isolated on and off dimeric effectors reveals that, in the kinase-on state, the HAMP is more conformationally destabilized compared with the PIR, whereas in the kinase-off state, the HAMP is more compact, and the PIR samples a greater breadth of conformations. On and off HAMP states produce different conformational effects at the KCM junction, but these differences decrease through the adaptation region and into the hinge only to return with the inverted relationship in the PIR. Continuous wave-ESR of the spin-labeled proteins confirms that broader PDS distance distributions correlate with increased rates of dynamics. Conformational breadth in the adaptation region changes with charge alterations caused by modification enzymes. Activating modifications broaden the HAMP conformational ensemble but correspondingly, compact the PIR. Thus, chemoreceptors behave as coupled units, in which dynamics in regions proximal and distal to the membrane change coherently but with opposite sign.chemotaxis | transmembrane signaling receptor | allostery | dynamics | adaptation T he ability of localized dynamics to modulate the function of transmembrane receptors is an emerging theme in signal transduction (1-4). These ideas have been largely supported by computational studies (2), although direct measurements also correlate dynamics with activity (1-4). Nonetheless, we are only beginning to address the link between conformational heterogeneity and signal propagation in complex proteins. Bacterial chemotaxis, the process by which cells modulate their motility in response to the chemical environment, provides an important model system to explore receptor dynamics experimentally (5, 6). During chemotaxis, attractant-bound chemoreceptors cause counterclockwise (CCW) flagella rotation and smooth swimming, whereas repellant-bound receptors cause clockwise flagella rotation and cell tumbling. Chemoreceptors, also termed methyl-accepting chemotaxis proteins, form extended arrays in the cytoplasmic membrane to communicate ligand binding (6) to the histidine kinase CheA and the coupling protein CheW. Great progress has been made in understanding how receptors communicate ligand-binding events across the cytoplasmic membrane, but h...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 99%

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Bacterial chemoreceptor dynamics correlate with activity state and are coupled over long distances

Samanta

Borbat

Dzikovski

et al. 2015

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

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“…Although the reason for this discrepancy is unclear, a two-residue deletion might induce torsional strain in the coiled-coil linker required for light regulation of PDE activity. For the parent receptor HsPDE2A, signal transduction was proposed to involve signal-dependent rearrangements of the interface between the two catalytic PDE subunits (13,33). In the absence of signal, a low-activity state is assumed, where the two PDE subunits are spatially arranged such that their substratebinding pockets are occluded by a protein loop, denoted the H-loop.…”

Section: Discussionmentioning

confidence: 99%

“…An elegant solution to this problem is outlined in a recent essay (33). Effectors intrinsically exist in equilibrium between states of low activity and high activity, which we identify as T (tense) and R (relaxed) states, respectively (21,34,35).…”

Section: Discussionmentioning

confidence: 99%

Engineering of a red-light–activated human cAMP/cGMP-specific phosphodiesterase

Gasser¹,

Taiber

Yeh

et al. 2014

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

160

161

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Significance Sensory photoreceptors not only enable organisms to derive spatial and temporal cues from incident light but also provide the basis for optogenetics, which denotes the manipulation by light of living systems with supreme spatial and temporal resolution. To expand the scope of optogenetics, we have engineered the light-activated phosphodiesterase LAPD, which degrades the ubiquitous second messengers cAMP and cGMP in a red-light–stimulated manner. Both cAMP and cGMP are key to the regulation of manifold physiological responses, and LAPD now augurs red-light control over these processes. As we demonstrate for two eukaryotic systems, LAPD does not require any additional exogenous factors, and thus permits the light perturbation of living cells in hitherto unrealized ways.

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Functional and Structural Roles of Coiled Coils

Hartmann

2017

Subcellular Biochemistry

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Coiled coils appear in countless structural contexts, as appendages to small proteins, as parts of multi-domain proteins, and as building blocks of filaments. Although their structure is unpretentious and their basic properties are understood in great detail, the spectrum of functional properties they provide in different proteins has become increasingly complex. This chapter aims to depict this functional spectrum, to identify common themes and their molecular basis, with an emphasis on new insights gained into dynamic aspects.

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Regulated unfolding: a basic principle of intraprotein signaling in modular proteins

Cited by 45 publications

References 60 publications

Bacterial chemoreceptor dynamics correlate with activity state and are coupled over long distances

Bacterial chemoreceptor dynamics correlate with activity state and are coupled over long distances

Engineering of a red-light–activated human cAMP/cGMP-specific phosphodiesterase

Functional and Structural Roles of Coiled Coils

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