It has very recently been recognized that numerous proteins involved in membrane curvature (MC) sensing and regulation are also implicated in a variety of diseases. Thus, the need to understand how MC couples with cellular function has emerged as a focus area both from a basic research as well as a biomedical perspective. Several membrane-binding protein domains have been shown to be capable of generating MC. Some of the most prominent members of these protein domains are the Bin/amphiphysin/Rvs (BAR) and Epsin N-terminal homology (ENTH) domains. These domains have been found in numerous disease-related proteins. To date, studies of these proteins rely heavily on electron microscopy imaging. The mechanisms by which these domains couple to MC and in particular a quantitative understanding of the hypothesized mechanisms have remained elusive. Membrane curvature sensing and generating proteins can be distinguished by several different types of disease involvement mechanisms. Firstly, altered expression levels are often found in malignant cells. For example, down-regulation or mis-splicing of BAR domain-containing proteins is found in cancers of various organs. Secondly, specific point mutations are encountered in proteins related to MC. For example, several point mutations in the BAR domain of the protein BIN1 (amphiphysin-2) are found to be linked to centronuclear myopathy. These mutations have been connected with membrane tubulation (i.e. curvature generation) activity. Furthermore, mutations within SH3 domains of BAR proteins, or mutations in SH3 domain ligands, are linked to several diseases. Our goal is to understand how protein concentration affects MC sensing and MC generation, and by which mechanisms these phenomena are effected by wild type and strategically mutated proteins. We will also investigate how ligand/SH3 domain interactions couple to membrane curvature. In order to achieve this goal, we have developed a biophysical approach that allows us to separately quantify MC sensing and generation. Curvature sensing will be determined through fluorescence measurements. These will monitor curvature-dependent re-localization of membrane-binding proteins and their mutants on membranes with precisely adjustable curvature. MC generation will be quantified through probing mechanical aspects of bent membranes. We will focus on using micropipette-aspiration and optical trapping to manipulate cylindrical membranes pulled from vesicles that are either self-assembled or purified from cells. We will provide improved mechanistic understanding of our quantitative data by comparing them to statistical mechanical, thermodynamic and mechanical theories. Our studies will provide valuable insight into MC regulation and sensing by proteins which may aid in understanding the role that these proteins play in numerous diseases.

Public Health Relevance

Membrane proteins coupling with cellular membrane curvature are involved in numerous diseases, including Alzheimer's, Huntington's, and Parkinson's disease, arthritis, centronuclear myopathy, diabetes, epilepsy, mental retardation, stiff person syndrome, and several types of cancer. The field of experimental research into curvature regulation and sensing by peripheral proteins is currently dominated by qualitative observations and insufficient mechanistic understanding. This project aims at providing a quantitative understanding of membrane curvature sensing and generation of three important classes of proteins, including mutants that occur in diseases such as centronuclear myopathy and Parkinson's disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Chin, Jean
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Arts and Sciences
United States
Zip Code
Chen, Zhiming; Atefi, Ehsan; Baumgart, Tobias (2016) Membrane Shape Instability Induced by Protein Crowding. Biophys J 111:1823-1826
Shi, Zheng; Sachs, Jonathan N; Rhoades, Elizabeth et al. (2015) Biophysics of α-synuclein induced membrane remodelling. Phys Chem Chem Phys 17:15561-8
Chen, Zhiming; Shi, Zheng; Baumgart, Tobias (2015) Regulation of membrane-shape transitions induced by I-BAR domains. Biophys J 109:298-307
Shi, Zheng; Baumgart, Tobias (2015) Membrane tension and peripheral protein density mediate membrane shape transitions. Nat Commun 6:5974
Tourdot, Richard W; Ramakrishnan, N; Baumgart, Tobias et al. (2015) Application of a free-energy-landscape approach to study tension-dependent bilayer tubulation mediated by curvature-inducing proteins. Phys Rev E Stat Nonlin Soft Matter Phys 92:042715
Knorr, Roland L; Nakatogawa, Hitoshi; Ohsumi, Yoshinori et al. (2014) Membrane morphology is actively transformed by covalent binding of the protein Atg8 to PE-lipids. PLoS One 9:e115357
Shi, Zheng; Baumgart, Tobias (2014) Dynamics and instabilities of lipid bilayer membrane shapes. Adv Colloid Interface Sci 208:76-88
Chen, Zhiming; Chang, Ken; Capraro, Benjamin R et al. (2014) Intradimer/Intermolecular interactions suggest autoinhibition mechanism in endophilin A1. J Am Chem Soc 136:4557-64
Shen, Hongying; Giordano, Francesca; Wu, Yumei et al. (2014) Coupling between endocytosis and sphingosine kinase 1 recruitment. Nat Cell Biol 16:652-62
Wu, Tingting; Baumgart, Tobias (2014) BIN1 membrane curvature sensing and generation show autoinhibition regulated by downstream ligands and PI(4,5)P2. Biochemistry 53:7297-309

Showing the most recent 10 out of 17 publications