Protein trafficking and maturation regulate intramembrane proteolysis

AbstractIntramembrane-cleaving proteases (I-CLiPs) are membrane embedded proteolytic enzymes. All substrates identified so far are also membrane proteins, involving a number of critical cellular signaling as well as human diseases. After synthesis and assembly at the endoplasmic reticulum, membrane proteins are exported to the Golgi apparatus and transported to their sites of action. A number of studies have revealed the importance of the intracellular membrane trafficking in i-CLiP-mediated intramembrane proteolysis, not only for limiting the unnecessary encounter between i-CLiPs and their substrate but also for their cleavage site preference. In this review, we will discuss recent advances in our understanding of how each i-CLiP proteolysis is regulated by intracellular vesicle trafficking. This article is part of a Special Issue entitled: Intramembrane Proteases

Multi-harmonic optical comb generation

We present a novel optical comb generation technique based on the use of a multi-harmonic electrical signal for driving the MZM. The proposed scheme is highly power efficient and gives rise to square shaped combs of advanced flatness and side mode suppression ratio while maintaining a stable performance over a long time period

Structural Kinetic Modeling of Metabolic Networks

To develop and investigate detailed mathematical models of cellular metabolic processes is one of the primary challenges in systems biology. However, despite considerable advance in the topological analysis of metabolic networks, explicit kinetic modeling based on differential equations is still often severely hampered by inadequate knowledge of the enzyme-kinetic rate laws and their associated parameter values. Here we propose a method that aims to give a detailed and quantitative account of the dynamical capabilities of metabolic systems, without requiring any explicit information about the particular functional form of the rate equations. Our approach is based on constructing a local linear model at each point in parameter space, such that each element of the model is either directly experimentally accessible, or amenable to a straightforward biochemical interpretation. This ensemble of local linear models, encompassing all possible explicit kinetic models, then allows for a systematic statistical exploration of the comprehensive parameter space. The method is applied to two paradigmatic examples: The glycolytic pathway of yeast and a realistic-scale representation of the photosynthetic Calvin cycle.Comment: 14 pages, 8 figures (color

Presenilin-dependent intramembrane cleavage of ephrin-B1

BACKGROUND: Presenilin-dependent γ-secretase cleavage of several transmembrane proteins, including amyloid-β precursor protein and Notch, mediates the intramembrane proteolysis to liberate their intracellular domains that are involved in cellular signaling. Considering γ-secretase inhibitors as therapeutics for Alzheimer's disease, understanding the physiologically and biologically important substrate for γ-secretase activity in brains is emerging issue. To elucidate the molecular mechanism and physiological role of γ-secretase, we screened candidate molecules for γ-secretase substrates. RESULTS: We show that ephrin-B1, that participates in cell-cell repulsive and attractive signaling together with its Eph receptor, constitutively undergoes ectodomain shedding and that the residual membrane-tethered fragment is sequentially cleaved by γ-secretase to release the intracellular domain. Furthermore, overexpression of membrane-tethered ephrin-B1 caused protrusion of numerous cellular processes consisted of F-actin, that required the preservation of the most C-terminal region of ephrin-B1. In contrast, soluble intracellular domain translocated into the nucleus and had no effect on cell morphology. CONCLUSION: Our findings suggest that ephrin-B is a genuine substrate for γ-secretase and regulates the cytoskeletal dynamics through intramembrane proteolysis

Generation of very flat optical frequency combs from continuous-wave lasers using cascaded intensity and phase modulators driven by tailored radio frequency waveforms

We demonstrate a scheme, based on a cascade of lithium niobate intensity and phase modulators driven by specially tailored radio frequency waveforms to generate an optical frequency comb with very high spectral flatness. In this work we demonstrate a 10 GHz comb with ~40 lines with spectral power variation below 1-dB and ~60 lines in total. The number of lines that can be generated is limited by the power handling capability of the phase modulator, and this can be scaled without compromising the spectral flatness. Furthermore, the spectral phase of the generated combs in our scheme is almost purely quadratic which, as we will demonstrate, allows for very high quality pulse compression using only single mode fiber.Comment: 12 pages, 3 figures, replaced the older version with the published versio

Dynamical robustness of biological networks with hierarchical distribution of time scales

We propose the concepts of distributed robustness and r-robustness, well adapted to functional genetics. Then we discuss the robustness of the relaxation time using a chemical reaction description of genetic and signalling networks. First, we obtain the following result for linear networks: for large multiscale systems with hierarchical distribution of time scales the variance of the inverse relaxation time (as well as the variance of the stationary rate) is much lower than the variance of the separate constants. Moreover, it can tend to 0 faster than 1/n, where n is the number of reactions. We argue that similar phenomena are valid in the nonlinear case as well. As a numerical illustration we use a model of signalling network that can be applied to important transcription factors such as NFkB

Nanometer-precision surface metrology of millimeter-size stepped objects using full-cascade-linked synthetic-wavelength digital holography using a line-by-line full-mode-extracted optical frequency comb

Digital holography (DH) is a powerful tool for surface profilometry of objects with sub-wavelength precision. In this article, we demonstrate full-cascade-linked synthetic-wavelength DH (FCL-SW-DH) for nanometer-precision surface metrology of millimeter-size stepped objects. 300 modes of optical frequency comb (OFC) with different wavelengths are sequentially extracted at a step of mode spacing from a 10GHz-spacing, 3.72THz-spanning electro-optic modulator OFC (EOM-OFC). The resulting 299 synthetic wavelengths and a single optical wavelength are used to generate a fine-step wide-range cascade link covering within a wavelength range of 1.54 um to 29.7 mm. We determine the 0.1000mm-stepped surface with axial uncertainty of 6.1 nm within the maximum axial range of 14.85 mm.Comment: 22 pages, 6 figure