Abstract
Pex11 proteins are involved in membrane elongation and division processes associated with the multiplication of peroxisomes. Human Pex11pβ has recently been linked to a new disorder affecting peroxisome morphology and dynamics. Here, we have analyzed the exact membrane topology of Pex11pβ. Studies with an epitope-specific antibody and protease protection assays show that Pex11pβ is an integral membrane protein with two transmembrane domains flanking an internal region exposed to the peroxisomal matrix and N- and C-termini facing the cytosol. A glycine-rich internal region within Pex11pβ is dispensable for peroxisome membrane elongation and division. However, we demonstrate that an amphipathic helix (Helix 2) within the first N-terminal 40 amino acids is crucial for membrane elongation and self-interaction of Pex11pβ. Interestingly, we find that Pex11pβ self-interaction strongly depends on the detergent used for solubilization. We also show that N-terminal cysteines are not essential for membrane elongation, and that putative N-terminal phosphorylation sites are dispensable for Pex11pβ function. We propose that self-interaction of Pex11pβ regulates its membrane deforming activity in conjunction with membrane lipids.
Highlights
Peroxisomes are single-membrane bound, multifunctional and highly dynamic organelles of most eukaryotic cells, which fulfil important metabolic functions in hydrogen peroxide and lipid metabolism
These observations confirm that the new Pex11pb antibody recognizes an epitope that is only accessible upon permeabilization of the peroxisomal membrane and lies protected within the peroxisomal matrix or membrane
Various topologies were proposed for Pex11 proteins in different organisms [38], [39], and the related Pex11pc was recently reported to dock on the cytosolic site of the peroxisomal membrane [20]
Summary
Peroxisomes are single-membrane bound, multifunctional and highly dynamic organelles of most eukaryotic cells, which fulfil important metabolic functions in hydrogen peroxide and lipid metabolism. Their function has been linked to developmental processes, stress response, age-related disorders, and antiviral innate immunity [1], [2], [3], [4], [5]. The assembly of peroxisomes and protein import into the organelle requires the action of essential proteins, so called peroxins, which are encoded by PEX genes. Mutations in many PEX genes have been identified as the cause of severe and often lethal peroxisome biogenesis disorders (e.g. Zellweger syndrome) [10], [11]
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