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Abstract
The destination of peroxisomal matrix proteins is encoded by short peptide sequences, which have been characterized as peroxisomal targeting signals (PTS) residing either at the C terminus (PTS1) or close to the N terminus (PTS2). PTS2-carrying proteins interact with their cognate receptor protein PEX7 that mediates their transport to peroxisomes by a concerted action with a co-receptor protein, which in mammals is the PTS1 receptor PEX5L. Using a modified version of the mammalian two-hybrid assay, we demonstrate that the interaction strength between cargo and PEX7 is drastically increased in the presence of the co-receptor PEX5L. In addition, cargo binding is a prerequisite for the interaction between PEX7 and PEX5L and ectopic overexpression of PTS2-carrying cargo protein drastically increases the formation of PEX7-PEX5L complexes in this assay. Consistently, we find that the peroxisomal transfer of PEX7 depends on cargo binding and that ectopic overexpression of cargo protein stimulates this process. Thus, the sequential formation of a highly stable trimeric complex involving cargo protein, PEX7 and PEX5L stabilizes cargo binding and is a prerequisite for PTS2-mediated peroxisomal import.
Highlights
Interaction between the type 2 peroxisomal targeting signal and its receptor initiates import of the cargo protein
In this article we identify the first point mutation in HsPEX7 that interferes with PEX5L binding and demonstrate that PEX5L binding is required to stabilize the interaction between PEX7 and PTS2carrying proteins
Because cargo binding has to precede the interaction between PEX7 and PEX5L, a defined sequence of interactions governs the peroxisomal import of PTS2-carrying proteins and avoids peroxisomal transport of cargo-free PEX7
Summary
Interaction between the type 2 peroxisomal targeting signal and its receptor initiates import of the cargo protein. The sequential formation of a highly stable trimeric complex involving cargo protein, PEX7 and PEX5L stabilizes cargo binding and is a prerequisite for PTS2-mediated peroxisomal import. All co-receptors harbor sequences for docking at the peroxisomal membrane and further integration [25, 26], and for ubiquitination and recycling of the co-receptor1⁄7receptor complex from peroxisomes to the cytosol [27, 28] From this perspective, PEX7 exerts a bridging function that links various cargo proteins harboring a PTS2 signal with the co-receptor protein such as PEX5L that mediates transport and receptor recycling. Thereby, we provide evidence that in PTS2-mediated protein import the interaction between PEX7 and cargo protein is a prerequisite for co-receptor binding, which reciprocally stabilizes the receptor-cargo interaction and initiates transfer of this complex to peroxisomes
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