Membrane shape is important not only as a static aspect of size and structure of cells and organelles, but dynamically changes in numerous processes such as membrane signaling and trafficking. At the plasma membrane, the formation of in- and exvaginations, in processes such as endocytosis and the generation of filopodia, respectively, are some of the most important phenomena where membrane curvature is modulated. The discovery of a class of proteins which contain crescent shaped scaffolds called BAR (Bin/amphiphysin/Rvs) domain proteins, has prompted a growing interest in understanding how proteins couple with membrane curvature. BAR domains are found in numerous proteins implicated in human disease, and many contain disease driving mutations and/or show altered expression levels under pathological conditions. Additional peripheral proteins that are related to membrane curvature include intrinsically disordered proteins such as ?-synuclein, as well as ENTH domain-containing proteins such as epsin, both of which are believed to be involved in membrane trafficking phenomena. Endocytosis is the primary mechanism by which pathogens enter cells. To improve the understanding of the mechanism and regulation of this process therefore is a matter of primary biomedical relevance. However, despite the fact that more than 90000 research contributions have investigated endocytosis alone, the mechanisms for initiation of this process are not understood. This is due in part to the fact that in cells numerous endocytic mechanisms operate in parallel and that the degree for experimental control of key parameters in cells is limited. The goal of this project is to understand how membrane shape transitions are regulated in processes such as endocytosis. In order to achieve this goal, we have developed an experimental biophysical model membrane approach that allows us to determine the conditions under which membranes undergo shape transitions. With the help of this tool, which consists of a combined micro- manipulation/fluorescence approach that is presently used exclusively in our laboratory, we will investigate mechanisms of the function of the many proteins involved in endocytosis, and isolate key modulators of membrane shape transitions. We already have developed a theoretical framework that will facilitate mechanistic interpretation of our findings. While plasma membranes experience significant asymmetry with respect to transmembrane ion and lipid distributions, model membrane research has largely focused on symmetric membranes. We will overcome this limitation and determine to what extent membrane asymmetry, which will include cytoskeletal interactions, contributes to the function of peripheral proteins in shaping membranes. Overall this project will provide far-reaching insight into the mechanisms by which peripheral proteins deform membranes under healthy and pathological conditions.

Public Health Relevance

Many peripheral membrane proteins key to creating and maintaining cellular membrane curvature are involved in a diverse array of devastating human disorders, including neurological diseases such as Alzheimer's, Huntington's, and Parkinson's disease, inflammatory and infectious diseases, centronuclear myopathy, metabolic diseases, and several types of cancer. Experimental research into curvature regulation and sensing by peripheral proteins is currently dominated by qualitative observations and insufficient mechanistic understanding. This project aims to improve the understanding how membrane shape is regulated in healthy and pathological conditions.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Chin, Jean
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University of Pennsylvania
Schools of Arts and Sciences
United States
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Wilner, Samantha E; Xiao, Qi; Graber, Zachary T et al. (2018) Dendrimersomes Exhibit Lamellar-to-Sponge Phase Transitions. Langmuir 34:5527-5534
Jankowska, Katarzyna I; Williamson, Edward K; Roy, Nathan H et al. (2018) Integrins Modulate T Cell Receptor Signaling by Constraining Actin Flow at the Immunological Synapse. Front Immunol 9:25
Liu, Chun; Deb, Sanghamitra; Ferreira, Vinicius S et al. (2018) Kinetics of PTEN-mediated PI(3,4,5)P3 hydrolysis on solid supported membranes. PLoS One 13:e0192667
Ramakrishnan, N; Sreeja, K K; Roychoudhury, Arpita et al. (2018) Excess area dependent scaling behavior of nano-sized membrane tethers. Phys Biol 15:026002
Xiao, Qi; Sherman, Samuel E; Wilner, Samantha E et al. (2017) Janus dendrimersomes coassembled from fluorinated, hydrogenated, and hybrid Janus dendrimers as models for cell fusion and fission. Proc Natl Acad Sci U S A 114:E7045-E7053
Graber, Z T; Shi, Z; Baumgart, T (2017) Cations induce shape remodeling of negatively charged phospholipid membranes. Phys Chem Chem Phys 19:15285-15295
Haney, Conor M; Cleveland, Christina L; Wissner, Rebecca F et al. (2017) Site-Specific Fluorescence Polarization for Studying the Disaggregation of ?-Synuclein Fibrils by Small Molecules. Biochemistry 56:683-691
Li, Ningwei; Sharifi-Mood, Nima; Tu, Fuquan et al. (2017) Curvature-Driven Migration of Colloids on Tense Lipid Bilayers. Langmuir 33:600-610
Chen, Zhiming; Atefi, Ehsan; Baumgart, Tobias (2016) Membrane Shape Instability Induced by Protein Crowding. Biophys J 111:1823-1826
Chen, Zhiming; Zhu, Chen; Kuo, Curtis J et al. (2016) The N-Terminal Amphipathic Helix of Endophilin Does Not Contribute to Its Molecular Curvature Generation Capacity. J Am Chem Soc 138:14616-14622

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