Abstract
Pex11, an abundant peroxisomal membrane protein (PMP), is required for division of peroxisomes and is robustly imported to peroxisomal membranes. We present a comprehensive analysis of how the Pichia pastoris Pex11 is recognized and chaperoned by Pex19, targeted to peroxisome membranes and inserted therein. We demonstrate that Pex11 contains one Pex19-binding site (Pex19-BS) that is required for Pex11 insertion into peroxisomal membranes by Pex19, but is non-essential for peroxisomal trafficking. We provide extensive mutational analyses regarding the recognition of Pex19-BS in Pex11 by Pex19. Pex11 also has a second, Pex19-independent membrane peroxisome-targeting signal (mPTS) that is preserved among Pex11-family proteins and anchors the human HsPex11γ to the outer leaflet of the peroxisomal membrane. Thus, unlike most PMPs, Pex11 can use two mechanisms of transport to peroxisomes, where only one of them depends on its direct interaction with Pex19, but the other does not. However, Pex19 is necessary for membrane insertion of Pex11. We show that Pex11 can self-interact, using both homo- and/or heterotypic interactions involving its N-terminal helical domains. We demonstrate that Pex19 acts as a chaperone by interacting with the Pex19-BS in Pex11, thereby protecting Pex11 from spontaneous oligomerization that would otherwise cause its aggregation and subsequent degradation.
Highlights
Accepted: 28 December 2021Peroxisomes are involved in long-chain fatty acid oxidation and ROS balance [1]
In yeast, such as Saccharomyces cerevisiae, Hansenula polymorpha, or Penicillium chrysogenum, the Pex19-BS is located near the Nterminal end [36], while in mammalian Pex11 isoforms, it is near the C-terminus [24,41,42]
We present a detailed analysis of the P. pastoris Pex11 protein and its interaction with the chaperone Pex19, which is required for Pex11 insertion into peroxisomal membrane, but not essential for its trafficking to the peroxisome surface
Summary
Peroxisomes are involved in long-chain fatty acid oxidation and ROS balance [1]. Due to their variable function, they are versatile organelles whose size, shape, and number, as well as content, adapt to environmental requirements [2,3]. Peroxisomes are maintained by proliferation of pre-existing peroxisomes or by de novo synthesis from the endoplasmic reticulum (ER) [4,5] Both pathways contribute to the cellular pool of peroxisomes and require the import of peroxisomal membrane proteins (PMPs) [6,7,8]. Pex serves only as the PMP import receptor, membrane structures [26,27,28,29]. Pex serves as the PMP import receptor, butsignals as and as a chaperone that interacts with their membrane peroxisome-targeting a chaperonemPTSs) that interacts with their membrane peroxisome-targeting In the yeast Pichia pastoris ( renamed Komagataella phaffi), named Komagataella phaffi), Pex seems not to function solely as a PMP protein import. Trafficking to the peroxisome ing to the peroxisome membrane could use non-canonical mechanisms, independent membrane could use non-canonical mechanisms, independent of direct Pex binding.of direct Pex binding
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