Ceramide-transfer protein-mediated ceramide transfer is a structurally tunable flow-inducing mechanism with structural feed-forward loops

Abstract

This paper considers two models of ceramide-transfer protein (CERT)-mediated ceramide transfer at the trans-Golgi network proposed in the literature, short distance shuttle and neck swinging, and seeks structural (parameter-free) features of the two models, which rely exclusively on the peculiar interaction network and not on specific parameter values. In particular, it is shown that both models can be seen as flow-inducing systems, where the flows between pairs of species are tuned by the concentrations of other species, and suitable external inputs can structurally regulate ceramide transfer. In the short distance shuttle model, the amount of transferred ceramide is structurally tuned by active protein kinase D (PKD), both directly and indirectly, in a coherent feed-forward loop motif. In the neck-swinging model, the amount of transferred ceramide is structurally tuned by active PI4KIIIβ, while active PKD has an ambivalent effect, due to the presence of an incoherent feed-forward loop motif that directly inhibits ceramide transfer and indirectly promotes it; the structural role of active PKD is to favour CERT mobility in the cytosol. It is also shown that the influences among key variables often have structurally determined steady-state signs, which can help falsify the models against experimental traces.

Structure, functions and regulation of CERT, a lipid‐transfer protein for the delivery of ceramide at the ER–Golgi membrane contact sites

“…To validate the model, multidisciplinary approaches, including conventional biochemical and genetic analyses, and computational simulation analysis should be encouraged. Simulation studies on CERT have been recently published .…”

BDC-Decomposition for Global Influence Analysis

“…Assessing whether all the systems with a given structure share a relevant structural property [4], [7], [16] helps explain how biological networks in nature preserve fundamental behaviours in the most diverse environmental conditions by design, independent of parameter values [4], [23], [27], [30], and also enables the rational design of robust artificial biomolecular networks in synthetic biology [9]. This paper focuses on the investigation of structurally signed input-output influences among the dynamic components of a biological network [17], [18], [19], [20], [21]. When a persistent positive input is applied to the system, the steadystate variation of the output variable can be either positive, negative, or zero: the influence is structural if the sign of the variation is independent of parameter values, while it is sign-indeterminate otherwise.…”

“…Research efforts are currently devoted to efficiently compute input-output influences [8], [25], [26]. Structural influence analysis enables us to predict steadystate behaviours that arise, regardless of the specific parameter values, in view of the system structure (when it is correctly known); while, given an uncertain 'conjectured' structure, the disagreement between structural predictions and experimental data allows for model falsification [17], [2].…”

Unraveling energy homeostasis in a dynamic model of glycolysis in Escherichia coli

“…How does the new steadystate differ from the previous one? For systems admitting a BDC-decomposition, the sign of the variation between the old and the new steady-states can be computed based on the algorithm proposed in [14] (see also the extension [9] and the applications to biological systems in [13], [15], [16], [17]).…”