A combined computational and structural model of the full-length human prolactin receptor

Bugge, Katrine; Papaleo, Elena; Haxholm, Gitte W.; Hopper, Jonathan T. S.; Robinson, Carol V.; Olsen, Johan G.; Lindorff‐Larsen, Kresten; Kragelund, Birthe B.

doi:10.1038/ncomms11578

Cited by 63 publications

(75 citation statements)

References 73 publications

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“…This tilt and change in length however did not correspond with any significant bending of the helix, or noticeable loss of residues involved in the helix. This is consistent with the NMR structure of the human PRLR transmembrane domain, which only bent as much as 6° [12]. The authors of this NMR structure also noted the PRLR transmembrane domain was embedded from residues 211 to 234 in 1,2-diheptanoyl-sn-glycero-3-phosphocholine (DHPC), a short chain lipid, which is in agreement with what was observed in these simulations.…”

Section: 7supporting

confidence: 80%

“…This has been confirmed experimentally for the human and mouse EPOR [10,11] and human prolactin receptor (PRLR) [12] in micelles by NMR spectroscopy. The helical nature of the transmembrane domain has been exploited in chimeric constructs in which the mouse erythropoietin receptor (mEpoR) and human GHR transmembrane domains are attached to leucine zippers from transcription factors [21,17,18].…”

Section: Introductionmentioning

confidence: 57%

“…Instead, as in the case of the EPOR, only X-ray crystallographic structures of the soluble extracellular domains (referred to as soluble erythropoietin receptor (sEPOR), residues 1-226) [5,6,7,8,9] and an NMR structure of the transmembrane domain in a micelle [10,11] have been reported. To date only the prolactin receptor (PRLR) has been been modelled as full-length receptor by piecing together X-ray crystal data for the extracellular domain and NMR data for the transmembrane and intracellular domains [12]. However, the use of this model either as a single chain or in a dimer complex to study the motions involved in the activation of the receptor has not been performed.…”

Section: 1mentioning

confidence: 99%

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Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Corbett¹

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The ability of a cell to recognise and respond to external stimuli is essential for cell survival and growth. Type-I cytokine receptors regulate many inflammatory, homeostatic, and growth and development signalling pathways. For example, the erythropoietin receptor is the main driver of red blood cell production from stem cells. All type-I cytokine receptors consist of an extracellular ligandbinding domain, a single helical transmembrane domain and an intracellular domain that associates with kinase/transcription factor signalling pathway, for example the JAK2/STAT5 pathway. Despite being extensively studied and structures of the extracellular domains of many of these receptors being known, the precise mechanism by which these receptors couple the event of ligand-binding to intracellular activation is not known. Indeed, multiple mechanisms have been proposed from experimental and crystallographic data for different receptors. For example, the activation of the growth hormone receptor is proposed to involve a relative rotation of two receptor chains, while in the case of the erythropoietin receptor the chains were suggested to separate in a scissor-like mechanism. In part, this is due to the limits of resolution achievable by experimental approaches as well as a lack of appreciation for the dynamical properties of the receptor proteins and the membrane environment.This thesis focuses on the use of fully atomistic molecular dynamics simulations to investigate the mechanism of activation for the type-I cytokine receptors. In particular MD simulations are used to probe whether conformations of the receptors observed crystallographically are representative of physiological conformations. Further to this, the quality of the X-ray crystal structures is tested by recreation of the crystal lattice in MD simulations. The effect of membrane composition is investigated by comparing the behaviour of the transmembrane domain in bulk and cholesterol-enriched raft-like bilayers. Finally, receptor dimers are examined for active and inactive conformations in raft-like bilayers containing sphingomyelin. Force field parameters for the lipid sphingomyelin that were used to build raft-like bilayers were also generated and validated. The work draws into question several of the mechanistic models proposed for the type-I cytokine receptors and demonstrates the difficulty in proposing a detailed mechanism of action based on limited sets of structural data. In particular, they highlight the limitations of the use of structural data in proposing a model when only a part of the receptor is considered. Results from the simulations also suggest that the lipid composition can influence the structure and behaviour of the receptors. Taken together the work shows the importance of considering not only the ligand-binding domain of the receptor but also the restrictions imposed by the transmembrane domain and structural influences caused by the membrane when proposing a mechanism of activation for this important class of cell surface recept...

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Section: 7supporting

confidence: 80%

Section: Introductionmentioning

confidence: 57%

Section: 1mentioning

confidence: 99%

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Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Corbett¹

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“…It is well known that across the plasma membrane of a living cell, a resting membrane potential is maintained by intercellular chemical processes [28]. It is also well known that within the plasma membrane there exist highly stable transmembrane regions of proteins, for instance the human prolactin receptor 2N7I [29], and the rat monoamine oxidase A 1O5W [30], both of which are α-helical structures spanning the entire membrane width. Given a constant potential difference of ΔV across a linear, homogeneous, isotropic dielectric medium with constant width d, the effective electric field inside the medium is given by E 0 = ΔV /(κd), where κ is the dielectric constant (a.k.a.…”

Section: Discussionmentioning

confidence: 99%

A generalised Davydov-Scott model for polarons in linear peptide chains

Luo

Piette

2017

Eur. Phys. J. B

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Abstract. We present a one-parameter family of mathematical models describing the dynamics of polarons in periodic structures, such as linear polypeptides, which, by tuning the model parameter, can be reduced to the Davydov or the Scott model. We describe the physical significance of this parameter and, in the continuum limit, we derive analytical solutions which represent stationary polarons. On a discrete lattice, we compute stationary polaron solutions numerically. We investigate polaron propagation induced by several external forcing mechanisms. We show that an electric field consisting of a constant and a periodic component can induce polaron motion with minimal energy loss. We also show that thermal fluctuations can facilitate the onset of polaron motion. Finally, we discuss the bio-physical implications of our results.

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“…Greater insight into the structure of the PRLR was recently determined, with the PRLR serving as the archetype of the structure of cytokine class-1 receptors (Haxholm et al 2015, Bugge et al 2016 (Fig. 2).…”

Section: Prlr Structure and Prlr Isoformsmentioning

confidence: 99%

Prolactin receptor in breast cancer: marker for metastatic risk

Shemanko

2016

Journal of Molecular Endocrinology

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Prolactin and prolactin receptor signaling and function are complex in nature and intricate in function. Basic, pre-clinical and translational research has opened up our eyes to the understanding that prolactin and prolactin receptor signaling function differently within different cellular contexts and microenvironmental conditions. Its multiple roles in normal physiology are subverted in cancer initiation and progression, and gradually we are teasing out the intricacies of function and therapeutic value. Recently, we observed that prolactin has a role in accelerating the time to bone metastasis in breast cancer patients and identified the mechanism by which prolactin stimulated breast cancer cellmediated lytic osteoclast formation. The possibility that the prolactin receptor is a marker for metastasis, and specifically bone metastasis, is one that may have to be put into the context of the different variants of prolactin, different prolactin receptor isoforms and intricate signaling pathways that are regulated by the microenvironment. The more complete the picture, the better one can test biomarker identity and design clinical trials to test therapeutic intervention. This review will cover the recent advances and highlight the complexity of prolactin receptor biology.

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A combined computational and structural model of the full-length human prolactin receptor

Cited by 63 publications

References 73 publications

Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

A generalised Davydov-Scott model for polarons in linear peptide chains

Prolactin receptor in breast cancer: marker for metastatic risk

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