Assistant Professor CHNG SHU SIN
|| B.Sc. (Hons), National University of Singapore, 2000-2003
Ph.D., Harvard University, 2004-2010
Postdoctoral fellow, Harvard Medical School, 2010-2011
| Department of Chemistry, NUS
3 Science Drive 3
| Office: MD1-14-03C
Tel: (65) 6516- 2682
Fax: (65) 67791691
Position Openings - NEW!!!
(updated Feb 2017)
We are seeking highly-motivated individuals who wish to pursue research in the field of membrane assembly and biochemistry. Positions are available at both the graduate and postdoctoral levels; a postdoctoral fellow position is available starting February 2017 (more information can be found here). Interested applicants should email enquiries and/or required documents to Shu Sin at email@example.com.
Our research program lies at the interface of chemistry and biology, and involves the use of chemical, biochemical and genetic approaches to characterize both the chemistry and molecular biology of a given system. The question that our group is interested in studying is membrane biogenesis, i.e.
how a biological membrane is assembled. Membrane lipid bilayers form the basis for life, physically defining cells and organelles, and modulating the chemical environments within these compartments for optimal metabolism and growth. Despite these fundamental roles, however, our understanding of membrane biogenesis has remained rudimentary; we do not know how a cell makes more of itself.
Bacterial outer membrane biogenesis - phospholipid transport
The outer membrane (OM) of Gram-negative bacteria represents an interesting system for studying membrane biogenesis. It is an asymmetric lipid bilayer containing lipopolysaccharide (LPS) in the outer leaflet and phospholipids (PLs) in the inner leaflet; the OM also contains β
-barrel proteins and lipoproteins (Figure 1). All four OM components are synthesized in the cytoplasm or the inner membrane (IM) and must be transported across the aqueous intermembrane space (periplasm) to be incorporated into the OM. The unique challenge of the Gram-negative organism is to assemble the OM outside the cytoplasm, in an environment that lacks an obvious energy source (i.e.
Figure 1. (A) High magnification electron micrograph of the E. coli K-12 cell envelope showing the OM (short arrow) and the IM (long arrow). (B) Schematic of the Gram-negative cell envelope showing the IM bilayer with integral and peripheral proteins, the cell wall and the asymmetric OM with PL, LPS, beta-barrel proteins and lipoproteins.
An outstanding question in OM biogenesis relates to PL transport from the IM to the OM, which represents the key process in membrane biogenesis in general. Surprisingly, very little is known about how PL, the most basic membrane building block, gets to its final destination in the inner leaflet of the OM (Figure 2). Therefore, research in our research group is directed towards elucidating the mechanism of PL transport in the model Gram-negative organism Escherichia coli
. Our immediate goals are to identify the protein machinery that is responsible for PL transport and to distinguish between different possible modes of PL transport from the IM to the OM. Eventually, we aim to be able to reconstitute PL transport in a biochemical system, and to begin addressing mechanistic questions about the transport process.
Figure 2. PL transport from the IM to the OM is not understood. Chemical structures of typical E. coli phospholipids are shown.
Gram-negative bacteria are able to live in harsh environments due to the presence of the OM, which serves as an effective permeability barrier that prevents toxic molecules. Many classes of antibiotics (macrolides, glycopeptides, etc
) are not effective in treating Gram-negative infections because they cannot penetrate the OM. Furthermore, resistance to effective drug classes (β
-lactams, fluoroquinolones, etc
) is already on the rise, underscoring the need to invent new strategies to fight Gram-negative pathogens. Since the OM is essential for the survival of these pathogens, and compromising OM integrity enables the use of many antibiotics currently only effective against Gram-positive pathogens, the molecular machines that build the OM have great potential as new targets for antibiotic discovery. A mechanistic understanding of how the OM is assembled would thus be extremely valuable.
- Shrivastava R, Jiang XE, Chng SS (2017) Bacterial outer membrane homeostasis via retrograde phospholipid transport. bioRxiv doi: 10.1101/109884. (link)
- Xu ZJ, Meshcheryakov VA, Poce G, Chng SS (2017) MmpL3 is the flippase for mycolic acids in mycobacteria. Proc Natl Acad Sci USA in press; preprint at bioRxiv doi: 10.1101/099440. (link)
- Thong SH, Ercan B, Torta F, Fong ZY, Wong HYA, Wenk MR, Chng SS (2016) Defining key roles for auxiliary proteins in an ABC transporter that maintains bacterial outer membrane lipid asymmetry. eLife 5:e19042. (link)
- Chong ZS, Woo WF, Chng SS (2015) Osmoporin OmpC forms a complex with MlaA to maintain outer membrane lipid asymmetry in Escherichia coli. Mol Micobiol 98:1133-1146. (link)
- Chng SS,* Xue M,* Garner RA, Kadokura H, Boyd D, Beckwith J, Kahne D (2012) Disulfide rearrangement triggered by translocon assembly controls lipopolysaccharide export. Science 337:1665-1668. (*equal contribution)
- Chng SS, Dutton, RJ, Denoncin K, Vertommen D, Collet JF, Kadokura H, Beckwith J (2012) Overexpression of the rhodanese PspE, a single cysteine-containing protein, restores disulfide bond formation to an Escherichia coli strain lacking DsbA. Mol Microbiol 85:996-1006.
Chimalakonda G, Ruiz N, Chng SS, Garner RA, Kahne D, Silhavy TJ (2011) Lipoprotein LptE is required for the assembly of LptD by the β-barrel assembly machine in the outer membrane of Escherichia coli.
Proc Natl Acad Sci USA 108:2492-2497.
Freinkman E, Chng SS, Kahne D (2011) The complex that inserts lipopolysaccharide into the bacterial outer membrane forms a two-protein plug-and-barrel. Proc Natl Acad Sci USA 108:2486-2491.
Ruiz N, Chng SS, Hiniker A, Kahne D, Silhavy TJ (2010) Non-consecutive disulfide bond formation in an essential integral outer membrane protein. Proc Natl Acad Sci USA 107:12245-12250.
Chng SS,* Gronenberg LS,* Kahne D (2010) Proteins required for lipopolysaccharide assembly in Escherichia coli form a trans-envelope complex. Biochemistry 49:4565-4567. (*equal contribution)
Chng SS, Ruiz N, Chimalakonda G, Silhavy TJ, Kahne D (2010) Characterization of the two-protein complex in Escherichia coli responsible for lipopolysaccharide assembly at the outer membrane. Proc Natl Acad Sci USA 107:5363-5368.
Wu T, McCandlish AC, Gronenberg LS, Chng SS, Silhavy TJ, Kahne D (2006) Identification of a protein complex that assembles lipopolysaccharide in the outer membrane of Escherichia coli. Proc Natl Acad Sci USA 103:11754-11759.