A mechanistic switch from selective transporter to an ion channel impairs the filamentation signalling capability of ammonium transceptors in yeast

Ammonium translocation through biological membranes by the ubiquitous Amt-Mep-Rh family of transporters plays a key role in all domains of life. Two highly conserved histidine residues protrude into the lumen of these transporters, forming the family’s characteristic Twin-His motif. It has been hypothesized that the motif is essential to confer the selectivity of the transport mechanism. Here, using a combination of in vitro electrophysiology, in vivo yeast functional complementation and in silico molecular dynamics simulations, we demonstrate that variations in the Twin-His motif trigger a mechanistic switch between a specific transporter, depending on ammonium deprotonation, to an unspecific ion channel activity. We therefore propose that there is no selective filter that governs the specificity in Amt-Mep transporters but the inherent mechanism of translocation, dependent on the fragmentation of the substrate, ensures the high specificity of the translocation. We further show that both mechanisms coexist in fungal Mep2 Twin-His variants, disrupting the transceptor function and so inhibiting the filamentation process. These data strongly support a transport mechanism-mediated signalling process in the long-standing debate on the sensory function of Mep2-like transporters.

A mathematical model of the role of aggregation in sonic hedgehog signalling

Effective regulation of the sonic hedgehog (Shh) signalling pathway is essential for normal development in a wide variety of species. Correct Shh signalling requires the formation of Shh aggregates on the surface of producing cells. Shh aggregates subsequently diffuse away and are recognised in receiving cells located elsewhere in the developing embryo. Various mechanisms have been postulated regarding how these aggregates form and what their precise role is in the overall signalling process. To understand the role of these mechanisms in the overall signalling process, we formulate and analyse a mathematical model of Shh aggregation using nonlinear ordinary differential equations. We consider Shh aggregate formation to comprise of multimerisation, association with heparan sulfate proteoglycans (HSPG) and binding with lipoproteins. We show that the size distribution of the Shh aggregates formed on the producing cell surface resembles an exponential distribution, a result in agreement with experimental data. A detailed sensitivity analysis of our model reveals that this exponential distribution is robust to parameter changes, and subsequently, also to variations in the processes by which Shh is recruited by HSPGs and lipoproteins. The work demonstrates the time taken for different sized Shh aggregates to form and the important role this likely plays in Shh diffusion.

From the ancient Silk Road to the belt and road initiative: Narratives, signalling and trust-building

Narratives help in interpreting and understanding surrounding political realities. Yet, the divergence of narratives may also create distrust, and it is an important reason for greatly diverging perceptions of the Belt and Road Initiative between China and the international community. This article explores how trust can be bridged between different narratives. It discusses the notions of trust and how the Chinese concept of ‘brightness’ contributes to a strategic signalling process for trust-building in strategic cooperation. This article proposes that trust-building is a process of signalling and knowledge building. Only when the signal sent for strategic cooperation fits the other parties’ knowledge about the sender, can the trust-building process succeed. This compatibility between signals and developed knowledge can be the result of several rounds of signalling, in which the signal sender’s honesty regarding their self-interests and intentions is the necessary pre-condition.

Managing noise in signalling effectiveness: an empirical test of listed companies in China

Purpose Signalling theory suggests how “strong” or “weak” the signal quality detected by a receiver (defined as signalling strength) is distorted by noisy factors (defined as noise). Although corporate cooperation signals are known to lead to receiver reaction, the effects of distortion factors on signal credibility are generally unexplored in signalling process. The paper aims to discuss this issue. Design/methodology/approach After analysing 264 contract announcements in 2013–2015 that befall publicly listed firms in China, the authors explore the signalling impact of contract value. the authors also incorporate the signalling noises, namely, signalling environment, external referents and other signallers, into the contracting context and investigate their effects on distorting the relationship between signal strength and receiver reaction. Findings Results indicate that firms’ contract-signing announcement conveys an effective signal to investors: the larger the contract scale is, the more investor reaction the firms experience. The signalling effects of contract scale on investor reaction are moderated by the three distorting factors. Originality/value The findings contribute to the signalling theory literature on the effects of signalling noise on receivers’ perception of signal observability.

Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity by a still not fully understood mechanism. We find that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones and increases longevity. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) and is not additive to the longevity of germline-less mutants. Noteworthy, sul-2 mutations do not affect fertility. Thus, STS inactivation affects the germline signalling process regulating longevity. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of germline longevity by environmental cues. We also demonstrate that treatment with the specific STS inhibitor STX64, reproduces the longevity phenotype of sul-2 mutants. Remarkably, STS inhibition by either mutation or drug treatment ameliorates protein aggregation diseases in C. elegans models of Parkinson, Huntington and Alzheimer, as well as Alzheimer disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors for the treatment of aging and aging related diseases.

Non-canonical Wnt signalling initiates scarring in biliary disease

Cholangiopathies, or biliary diseases, account for a significant proportion of adult and paediatric liver disease. In these pathologies, iterative cycles of damage and repair result in the development of a regenerative microenvironment surrounding the bile ducts, which orchestrates both epithelial proliferation and also biliary fibrosis. Ultimately, fibrosis at the cost of repair results in cholestasis and liver failure, necessitating liver transplantation. Whilst the fibrogenic mechanisms in hepatocellular disease have been widely studied, little is known about the processes that regulate biliary scarring. We sought to determine how the injured biliary epithelium communicates to adjacent stromal cells to regulate scar formation, and to identify therapeutically targetable pathways that could be inhibited to reduce biliary scarring, whilst maintaining the pro-regenerative stroma. Using human tissue, bile duct organoids and animal models of biliary disease, we show that non-canonical Wnt signalling is important in initiating biliary scarring. This process is driven by myeloid Wnt5a and acts through epithelial Vangl2, which is upstream of Jnk/cJun signalling. Activation of this pathway drives a pro-fibrotic signalling process which instructs portal fibroblasts to synthesise collagen. Finally, we determine that therapeutic Wnt ligand inhibition reduces biliary scarring, identifying non-canonical Wnt signalling as a novel target for anti-fibrotic therapy in cholestatic biliary disease.

Allosteric signalling paths in hemoglobin: a protein dynamics network analysis

Hemoglobin is the paradigm of cooperative protein-ligand binding. Cooperativity is the consequence of inter-subunit allosteric communication: binding at one site increases the affinity of the others. Despite half a century of studies, the mechanism behind oxygen binding in hemoglobin is not fully understood yet. In particular, it is not clear if cooperativity arises from preferential inter-subunit channels and which residues propagate the allosteric signal from one heme to the others. In this work, the heme-heme dynamical interactions have been mapped through a network-based analysis of residue conformational fluctuations, as described by molecular dynamics simulations. In particular, it was possible to suggest which inter-subunit interactions are mostly responsible of allosteric signalling and, within each pair of subunits, which protein fragments convey such signalling process.

Plant cytokinin signalling

Cytokinin is an essential plant hormone that is involved in a wide range of plant growth and developmental processes which are controlled through its signalling pathway. Cytokinins are a class of molecules that are N6-substituted adenine derivatives, such as isopentenyl adenine, and trans- and cis-zeatin, which are common in most plants. The ability to perceive and respond to cytokinin occurs through a modified bacterial two-component pathway that functions via a multi-step phosphorelay. This cytokinin signalling process is a crucial part of almost all stages of plant life, from embryo patterning to apical meristem regulation, organ development and eventually senescence. The cytokinin signalling pathway involves the co-ordination of three types of proteins: histidine kinase receptors to perceive the signal, histidine phosphotransfer proteins to relay the signal, and response regulators to provide signal output. This pathway contains both positive and negative elements that function in a complex co-ordinated manner to control cytokinin-regulated plant responses. Although much is known about how this cytokinin signal is perceived and initially regulated, there are still many avenues that need to be explored before the role of cytokinin in the control of plant processes is fully understood.