Membrane trafficking at atomic resolution

Our body’s cells contain a dynamic system of membranes responsible for the transport of materials into, out of, and from place to place within each cell.

This careful balancing act is how cells maintain homeostasis; proteins and other materials are deftly ‘trafficked’ from place to place, wherever they’re needed, performing a host of chemical and mechanical functions.

The concentrations of materials in any one place needs to be finely controlled if the cell is to function properly.

Essential to these transport processes, says Associate Professor Brett Collins, are many different types of peripheral membrane proteins.

Research overview

“These protein complexes are recruited to their sites of action through coordinated interactions with integral membrane proteins and lipids. If one of these complexes undergoes genetic mutation its ability to interact with trafficking membranes is diminished and it can no longer reach its target.

“Depending where the mutation occurs, this phenomenon can lead to a range of disorders including Alzheimer’s and Parkinson’s disease, epilepsy, cancer and muscular dystrophy.”

One focus of Associate Professor Collins’ study is the retromer complex.

Point mutations in retromer cause late-onset Parkinson’s disease, and retromer dysfunction is strongly correlated with Alzheimer’s disease.

The retromer complex is essential for the breakdown of toxic or aggregated cellular material, and if it is unable to do its job these molecules accumulate. In long-lived cells like those in the brain this can be disastrous.

New treatment options for neurodegenerative disease are still a long way off, and a better understanding of the atomic-level structure of the cellular machinery is needed.

“Working with other teams in the IMB and around the world, our Membrane Trafficking Group has made considerable progress towards this goal.

Also, molecular ‘chaperones’ that bind to the retromer complex show significant promise in restoring retromer’s ability to tackle the destructive compounds,” said Associate Professor Collins.

Associate Professor Collins and his team continue to explore the fundamental processes by which protein machineries regulate cellular membrane transport, and hope this knowledge may one day lead to more effective treatments for these neurodegenerative diseases and other disorders.

Research projects

Peripheral membrane proteins are essential for cellular trafficking and membrane remodeling, and have emerged as key determinants in many human disorders, including Alzheimer’s and Parkinson’s diseases, cancer, epilepsy and muscular dystrophy. This provides new opportunities for treating these conditions, but requires a much more detailed molecular understanding before such goals can be realised. Using cutting-edge structural, molecular and cellular approaches our lab aims to determine how these proteins control essential processes of cellular homeostasis, hormonal signaling, tissue morphogenesis, and neurosecretion in health and disease. 

The retromer complex in endosomal sorting and neurodegeneration.

The retromer complex is a peripheral membrane protein assembly that is essential for endosomal trafficking and is mutated in neurodegenerative diseases including Alzheimer’s and Parkinson’s. Our lab has made important contributions to the molecular understanding of retromer function and continues to use the techniques of X-ray crystallography and Electron Microscopy to study the principles that govern its assembly and dysfunction. 

Intracellular trafficking and membrane regulation by Sorting Nexins (SNXs).

Sorting nexins are a large and diverse family of proteins with various roles in intracellular membrane transport and cell signalling. Their dysfunction is implicated in diseases including cancer, inflammation, genetic disorders and Alzheimer's disease, and they are emerging as therapeutic targets in these disorders. We aim to discover their mechanisms of action and to determine their potential for therapeutic development. 

Caveola biogenesis and the role of the cavin proteins.

Caveolae are ~50 nm bud-like structures on the plasma membrane, with multiple roles in signal transduction, endocytosis and as sensors of membrane stress. In collaboration with Prof. Rob Partin (IMB, UQ) we aim to determine the molecular principles that govern the assembly of these critical protein-coated membrane vesicles. 

Regulation of neurosecretion by SNAREs and Munc18.

SNARE-mediated membrane fusion is required for regulated exocytosis and is critical in many cellular processes including neurosecretion, insulin secretion, immune responses and inflammation. The assembly of all SNARE complexes during membrane fusion is very tightly regulated by proteins of the Sec/Munc (SM) protein family that bind primarily to the syntaxin SNARE subunits and together with Prof. Jenny Martin (Griffith Uni) and Prof. Fred Meunier (QBI, UQ) we are attempting to define the pathways and molecular interactions of SNARE and SM proteins that regulate neuronal synaptic function. 

Research training opportunities

Summary of research interests:

Our group studies the process of membrane trafficking in the human cell. This is fundamental for normal physiology, and is important in neurodegenerative diseases including Alzheimer’s and Parkinson’s. Our goal is to determine the molecular basis of how ‘protein coats’ bind to receptors such as the amyloid precursor protein involved in Alzheimer’s and control their packaging into membrane-bound vesicles. We use a wide variety of techniques including molecular biology, protein X-ray crystallography, biochemical and biophysical studies of protein-protein and protein-lipid interactions, and cellular studies of protein localisation to build coherent molecular models of how molecules are trafficked within the cell.

Traineeships, honours and PhD projects include

  • Molecular basis for the function of the retromer protein complex, and implications for neurodegenerative diseases.
  • Determining the role of ‘sorting nexin’ proteins in controlling the homeostasis of receptors in neurons.
  • Discovery of small molecules that modulate the assembly of protein trafficking coats.
  • Structural studies of proteins that form membrane structures called caveolae.

Contact: Associate Professor Brett Collins

+61 7 3346 2043
b.collins@imb.uq.edu.au


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Engagement and impact

Membrane trafficking has in recent years become increasingly of interest to scientists and clinicians studying the onset of neurodegenerative disease, most especially with respect to Alzheimer’s and Parkinson’s where proteins such as retromer have been found to play a critical role. We aim to provide our expertise and the reagents we develop to the wider community, and contribute to the progress towards developing new approaches to target trafficking for therapeutic benefit. 

Our scientific discoveries have been published in high impact journals including Cell, Nature, and PNAS, and was recently the subject of awards from the Australian Society for Biochemistry and Molecular Biology and the Australian New Zealand Society for Cell and Developmental Biology. 

Partners and collaborators

We collaborate with a number of cell biology and structural biology groups in Australia and internationally.

Long-standing collaborators include:

  • Professor Robert Parton (Cell Biology, IMB, UQ)
  • Associate Professor Rohan Teasdale (Cell Biology, SBMS, UQ)
  • Dr Nathan Pavlos (Cell Biology, University of Western Australia)
  • Professor Fred Meunier (Neuronal trafficking, QBI, UQ)
  • Professor Lizzie Coulson (Mouse models of neuronal disease, SBMS, UQ)
  • Dr Victor Anggono (Neuronal trafficking, QBI, UQ)
  • Professor Pete Cullen (Cell biology, University of Bristol, UK).
  • Professor Isabel Merida (T-cell biology, CNB Barcelona, Spain)
  • Associate Professor Mehdi Mobli (NMR structures, CAI, UQ)
  • Professor Jenny Martin (GRIDD, Griffith University).
     

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A/Prof Brett Collins

Associate Professor Brett Collins

Group Leader, Cell Biology and Molecular Medicine Division

  +61 7 3346 2043  
  b.collins@imb.uq.edu.au
  IMB Researcher Profile


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