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Protein transport across and into peroxisomal membranes

Peroxisomes are metabolic organelles present in virtually all eukaryotic cells that fulfill a variety of cellular functions. Defects in peroxisome biogenesis cause severe, often lethal diseases in hu­mans emphasizing the importance of this organelle for cellular fitness. All peroxisomal proteins are nuclear-encoded and need to be posttranslationally imported into the organelle following syn­the­sis on cytosolic ribosomes. Proteins destined for the peroxisomal matrix generally carry one of two distinct peroxisomal targeting signals (PTS), which are recognized by specific receptor proteins in the cytosol (Fig. 1, left). The receptor-cargo complex is targeted to the peroxi­somal membrane and docks to a membrane-bound protein complex (Pex13/14/17p) followed by the dynamic formation of an import pore [1,2] that facilitates the translocation of folded and even oligomeric proteins. The receptor-cargo complex is disassembled and the cargo released into the lumen of the peroxisome. Subsequently, the membrane-bound receptor is exported back into the cytosol in a process that requires receptor ubiquitination and ATP [3]. Peroxisomal mem­brane proteins (PMPs) contain a membrane PTS and are recognized in the cytosol by the receptor Pex19p (Fig. 1, right). These so-called class I PMPs are directly targeted to peroxisomes by bin­ding of Pex19p-cargo to Pex3p followed by membrane insertion. In contrast, class II PMPs traffic through the endoplasmic reticulum (ER) and exit from a specialized ER compartment [3].

An important but so far largely unanswered question is how the overall process of peroxisomal protein transport is regulated. With the exception of PTS receptor ubiquitination required for their export and interlinked with protein import, information about posttranslational mechanisms modulating peroxisomal protein transport are scarce. We recently identified the Ser/Thr kinase Hrr25p as transient binding partner of import complexes [4]. In addition, we found that key com­po­nents of the peroxisomal matrix and membrane protein import machineries are phosphory­lated in vivo (Fig. 1; [5]). These observations suggest that protein phosphorylation provides a me­cha­nism by which peroxisomal protein translocation is modulated at the posttranslational level. In this project, we will study the role of reversible phosphorylation events mediated by cytosolic kinases for the regulation of protein transport across and into the peroxisomal membrane in the eukaryotic model organism Saccharomyces cerevisiae and in human cells.


Figure 1: Model of the translocation of matrix (left) and membrane (right) proteins into peroxisomes. Key components of both protein transport routes were found to be phosphorylated. PMP, peroxisomal membrane protein.



[1] Meinecke, M, Cizmowski, C, Schliebs, W, Kruger, V, Beck, S, Wagner, R, Erdmann, R (2010) Nat. Cell. Biol. 12: 273-277
[2] Montilla-Martinez, M, Beck, S, Klümper, J, Meinecke, M, Schliebs, W, Wagner, R, Erdmann, R (2015) Cell Rep. 13: 2126-2134
[3] Kim, PK, Hettema, EH (2015) Mol. Biol. 427: 1176-1190
[4] Oeljeklaus, S, Reinartz, BS, Wolf, J, Wiese, S, Tonillo, J, Podwojski, K, Kuhlmann, K, Stephan, C, Meyer, HE, Schliebs, W, Brocard, C, Erdmann, R, Warscheid, B (2012) J. Proteome Res. 11:2567-2580
[5] Oeljeklaus, S., Schummer, A., Mastalski, T., Platta, H.W., Warscheid, B. (2016) Biochim. Biophys. Acta 1863: 1027-1037



Prof. Dr. Bettina Warscheid

Institute of Biology II
Schänzlestr. 1
79104 Freiburg

Phone: +49 (761) 203 2690 
Fax: +49 (761) 203 2601