John CHUA

Interactomics and Intracellular Trafficking

Profile

John CHUA

John Chua obtained his B.Sc. (Honours) at the National University of Singapore (NUS) and his PhD at the University of Hamburg (Germany) where he worked on translational regulation at the post-synapse. As a postdoctoral fellow at the Max Planck Institute for Biophysical Chemistry in Göttingen, he studied the composition and organization of protein complexes involved in presynaptic function. He was appointed a Research Group Leader at the institute and a faculty member of the Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences (GGNB). In 2015, he joined the Department of Physiology at NUS as an Assistant Professor and IMCB as a joint PI.

Research

Interactomics and Intracellular trafficking

Protein Trafficking to Synapses

Neurotransmission occurs at specialized contact sites between neurons called synapses. Each synapse comprises over a thousand proteins that are delivered from their sites of synthesis via the intracellular trafficking machinery. The logistics of sorting and transporting proteins to meet the needs of the approximately 10,000 synapses distributed throughout numerous highly elongated neuronal processes represents a particularly challenging task. Disruption of intracellular trafficking and loss of synapses are frequently observed in neurodegenerative disorders and during the aging process. We uncovered an axonal transport pathway in which the Kinesin-1 adapter FEZ1 mediates delivery of Syntaxin-1 to synapses where it is required for synaptic vesicle exocytosis. Phosphorylation of FEZ1 regulates its function in this process. Strikingly, loss of FEZ1 function produces phenotypes reminiscent of defective transport observed in Alzheimer’s disease patients and mouse models. Using this system as a model of presynaptic trafficking, our research aims to identify components and regulatory pathways involved in protein trafficking during synapse formation and maintenance. In doing so, we seek to clarify how their defects contribute to synaptic malfunction and ultimately neurodegenerative disorders.

A working model for FEZ1's role in protein trafficking to synapses

Synaptic Interactomics

Ensembles of different proteins participate in various key nano-machineries functioning at the synapse. The lab is interested in identifying and studying how interactions between these proteins contribute to synaptic function and organization. We employed the yeast 2-hybrid system to probe for novel presynaptic interactions for a selection of presynaptic proteins. The interaction between FEZ1 and Syntaxin-1 described above is a direct outcome resulting from this effort. Studies are on-going to elucidate the functional significance of other newly identified interactions.

Publications

Recent Publications

Binotti B, Pavlos NJ, Riedel D, Wenzel D, Vorbrüggen G, Schalk AM, Kühnel K, Boyken J, Erck C, Martens H, *Chua JJ, *Jahn R. (2015)
The GTPase Rab26 links synaptic vesicles to the autophagy pathway.
Elife. 4:e0559
*Co-corresponding authors

Chua JJ. (2014)
Macromolecular complexes at active zones: integrated nano-machineries for neurotransmitter release.
Cell Mol Life Sci. 71: 3903-1

Behrens C, Binotti B, Schmidt C, Robinson CV, Chua JJ, Kühnel K. (2013)
Crystal structure of the human short coiled coil protein and insights into SCOC-FEZ1 complex formation.
PLoS One. 8: e7635

Boyken J, Grønborg M, Riedel D, Urlaub H, Jahn R, Chua JJ. (2013)
Molecular profiling of synaptic vesicle docking sites reveals novel proteins but few differences between glutamatergic and GABAergic synapses.
Neuron. 78: 285-29
Article selected by Faculty of 1000 (http://f1000.com/prime/718002648)

Chua JJ, Jahn R, Klopfenstein DR. (2013)
Managing Intracellular Transport.
Worm. 2: e21564.

Chua JJ, Schob C, Rehbein M, Gkogkas CG, Richter D, Kindler S. (2012)
Synthesis of two distinct SAPAP3 isoforms from a single mRNA is mediated via an upstream open reading frame and alternative translational initiation.
Sci. Rep. 2, 484; DOI:11038/ srep0048

Chua JJ, Butkevich E, Worseck JM, Kittelmann M, Grønborg M, Behrmann E, Stelzl U, Pavlos NJ, Lalowski M, Eimer S, Wanker EE, Klopfenstein D, Jahn R. (2012)
Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter.
Proc Natl Acad Sci U S A. 109: 5862- 586

Chua JJ, Kindler S, Boyken J, Jahn R. (2010)
The architecture of an excitatory synapse.
J Cell Sci. 123: 819-92

Pavlos NJ, Grønborg M, Riedel D, Chua JJ, Boyken J, Kloepper TH, Urlaub H, Rizzoli, SO, Jahn R. (2010)
Quantitative analysis of synaptic vesicle Rabs uncovers distinct yet overlapping roles of Rab3a and Rab27b in Ca2+-triggered exocytosis.
J Neurosci. 30: 13441-1345

Grønborg M, Pavlos NJ, Brunk I, Chua JJ, Münster-Wandowski A, Riedel D, Ahnert-Hilger G, Urlaub H, Jahn R. (2010)
Quantitative comparison of glutamatergic and GABAergic synaptic vesicles unveils selectivity for few proteins including MAL2, a novel synaptic vesicle protein.
J Neurosci. 30: 2- 12.

Barszczewski M, Chua JJ, Stein A, Winter U, Heintzmann R, Zilly FE, Fasshauer D, Lang T, Jahn R. (2008)
A novel site of action for α-SNAP in the SNARE conformational cycle controlling membrane fusion.
Mol Biol Cell. 19: 776-784.