The goal of the lab is to understand how the cell uses approximately 35 Pex proteins to make and maintain the peroxisome – a small, membrane-bound organelle that is conserved from yeast to humans.
Peroxisomes are metabolic organelles that typically perform the beta-oxidation of fatty acids, but are also remarkably specialized across cell type and species for a variety of functions. In humans, mutations in the pex genes cause a spectrum of disorders called Peroxisome Biogenesis Disorders.
Cells can adjust the size, number and function of their peroxisomes according to need. Remarkably, cells can completely lose their peroxisomes (for example by uneven segregation during cell division) and make a new peroxisome by de novo peroxisome biogenesis, essentially creating a new organelle from scratch.
Some of the questions we are interested in:
What are the energy-dependent steps of peroxisome biogenesis?
Pex1 and Pex6 are both AAA-ATPases, which are hexameric complexes that use the energy of ATP hydrolysis to unfold proteins, extract proteins from membranes, or unwind DNA. We recently showed that together Pex1 and Pex6 form a complex that can unfold another Pex protein – Pex15 – in vitro. However, it isn’t clear if Pex1/Pex6 unfolds Pex15 or other substrates in the cell or how their unfolding contributes to peroxisome biogenesis. We are taking unbiased approaches to identify Pex1/Pex6’s in vivo substrates.
How do proteins translocate across the peroxisomal membrane?
Unlike proteins that end up in the endoplasmic reticulum or mitochondria, peroxisomal matrix proteins are imported across the peroxisome membrane fully folded. Matrix proteins are first bound in the cytosol by the targeting signal receptors Pex5 or Pex7, brought to the peroxisome membrane, and subsequently imported through a poorly defined “importomer”. We are interested in characterizing the mechanisms of translocation of folded proteins across the peroxisome membrane.
How does peroxisomal dysfunction impact the cell?
The peroxisome generates and metabolizes reactive oxygen species and contributes to cellular metabolism. Therefore, perturbations in its function could cause significant cellular stress that is different from that caused by the absence of peroxisomes. We are interested in characterizing the cellular reaction to peroxisome stress and identifying proteins required for peroxisome maintenance.