Chen Zhu

Bio: Chen Zhu is an academic researcher from University of Pennsylvania. The author has contributed to research in topics: Curvature & Membrane curvature. The author has an hindex of 5, co-authored 6 publications receiving 531 citations. Previous affiliations of Chen Zhu include University of Science and Technology of China.

Thermodynamics and Mechanics of Membrane Curvature Generation and Sensing by Proteins and Lipids

Abstract: Research investigating lipid membrane curvature generation and sensing is a rapidly developing frontier in membrane physical chemistry and biophysics. The fast recent progress is based on the discovery of a plethora of proteins involved in coupling membrane shape to cellular membrane function, the design of new quantitative experimental techniques to study aspects of membrane curvature, and the development of analytical theories and simulation techniques that allow a mechanistic interpretation of quantitative measurements. The present review first provides an overview of important classes of membrane proteins for which function is coupled to membrane curvature. We then survey several mechanisms that are assumed to underlie membrane curvature sensing and generation. Finally, we discuss relatively simple thermodynamic/mechanical models that allow quantitative interpretation of experimental observations.

Coupling between endocytosis and sphingosine kinase 1 recruitment.

Abstract: Genetic studies have suggested a functional link between cholesterol/sphingolipid metabolism and endocytic membrane traffic. Here we show that perturbing the cholesterol/sphingomyelin balance in the plasma membrane results in the massive formation of clusters of narrow endocytic tubular invaginations positive for N-BAR proteins. These tubules are intensely positive for sphingosine kinase 1 (SPHK1). SPHK1 is also targeted to physiologically occurring early endocytic intermediates, and is highly enriched in nerve terminals, which are cellular compartments specialized for exo/endocytosis. Membrane recruitment of SPHK1 involves a direct, curvature-sensitive interaction with the lipid bilayer mediated by a hydrophobic patch on the enzyme's surface. The knockdown of SPHKs results in endocytic recycling defects, and a mutation that disrupts the hydrophobic patch of Caenorhabditis elegans SPHK fails to rescue the neurotransmission defects in loss-of-function mutants of this enzyme. Our studies support a role for sphingosine phosphorylation in endocytic membrane trafficking beyond the established function of sphingosine-1-phosphate in intercellular signalling.

The N-Terminal Amphipathic Helix of Endophilin Does Not Contribute to Its Molecular Curvature Generation Capacity.

Abstract: N-BAR proteins such as endophilin are thought to bend lipid membranes via scaffolding (the molding of membranes through the crescent protein shape) and membrane insertion (also called wedging) of amphipathic helices. However, the contributions from these distinct mechanisms to membrane curvature generation and sensing have remained controversial. Here we quantitatively demonstrate that the amphipathic N-terminal H0 helix of endophilin is important for recruiting this protein to the membrane, but does not contribute significantly to its intrinsic membrane curvature generation capacity. These observations elevate the importance of the scaffolding mechanism, rather than H0 insertion, for the membrane curvature generation by N-BAR domains. Furthermore, consistent with the thermodynamically required coupling between curvature generation and sensing, we observed that the H0-truncated N-BAR domain is capable of sensing membrane curvature. Overall, our contribution clarifies an important mechanistic controversy i...

Intradimer/Intermolecular Interactions Suggest Autoinhibition Mechanism in Endophilin A1

Abstract: Endophilin A1 is a homodimeric membrane-binding endocytic accessory protein with a high dimerization affinity. Its function has been hypothesized to involve autoinhibition. However, the autoinhibition mechanism, as well as the physicochemical basis for the high dimerization affinity of endophilin in solution, have remained unclear. In this contribution, we use a Forster resonance energy transfer (FRET) method to investigate the homodimerization mechanism and intradimer molecular interactions in endophilin. For the endophilin N-BAR domain (which lacks the SH3 domain including a linker region of the full length protein), we observe a large temperature dependence of the dimerization affinity and dimer dissociation kinetics, implying large dimerization enthalpy and dissociation activation enthalpy, respectively. Our evaluation of the protein concentration dependence of dimer dissociation kinetics implies that endophilin reversibly forms monomers via a dissociation/reassociation mechanism. Furthermore, we use ...

Sphingolipids and their metabolism in physiology and disease.

Abstract: Studies of bioactive lipids in general and sphingolipids in particular have intensified over the past several years, revealing an unprecedented and unanticipated complexity of the lipidome and its many functions, which rivals, if not exceeds, that of the genome or proteome. These results highlight critical roles for bioactive sphingolipids in most, if not all, major cell biological responses, including all major cell signalling pathways, and they link sphingolipid metabolism to key human diseases. Nevertheless, the fairly nascent field of bioactive sphingolipids still faces challenges in its biochemical and molecular underpinnings, including defining the molecular mechanisms of pathway and enzyme regulation, the study of lipid-protein interactions and the development of cellular probes, suitable biomarkers and therapeutic approaches.

Dynamin, a membrane-remodelling GTPase

Abstract: Dynamin, the founding member of a family of dynamin-like proteins (DLPs) implicated in membrane remodelling, has a critical role in endocytic membrane fission events. The use of complementary approaches, including live-cell imaging, cell-free studies, X-ray crystallography and genetic studies in mice, has greatly advanced our understanding of the mechanisms by which dynamin acts, its essential roles in cell physiology and the specific function of different dynamin isoforms. In addition, several connections between dynamin and human disease have also emerged, highlighting specific contributions of this GTPase to the physiology of different tissues.

Membrane bending by protein-protein crowding

Abstract: Membrane deformation is necessary to generate endocytic vesicles, but the molecular mechanisms proposed to drive membrane bending are controversial. Stachowiak and Schmid et al. report that crowding of proteins at the membrane is sufficient to induce curvature in vitro.

Computational Modeling of Realistic Cell Membranes

Abstract: Cell membranes contain a large variety of lipid types and are crowded with proteins, endowing them with the plasticity needed to fulfill their key roles in cell functioning. The compositional complexity of cellular membranes gives rise to a heterogeneous lateral organization, which is still poorly understood. Computational models, in particular molecular dynamics simulations and related techniques, have provided important insight into the organizational principles of cell membranes over the past decades. Now, we are witnessing a transition from simulations of simpler membrane models to multicomponent systems, culminating in realistic models of an increasing variety of cell types and organelles. Here, we review the state of the art in the field of realistic membrane simulations and discuss the current limitations and challenges ahead.