Abstract
The peroxisomal protein import machinery differs fundamentally from known translocons (endoplasmic reticulum, mitochondria, chloroplasts, bacteria) as it allows membrane passage of folded, even oligomerized proteins. However, the mechanistic principles of protein translocation across the peroxisomal membrane remain unknown. There are various models that consider membrane invagination events, vesicle fusion or the existence of large import pores. Current data show that a proteinaceous peroxisomal importomer enables docking of the cytosolic cargo-loaded receptors, cargo translocation and receptor recycling. Remarkably, the cycling import receptor Pex5p changes its topology from a soluble cytosolic form to an integral membrane-bound form. According to the transient pore hypothesis, the membrane-bound receptor is proposed to form the core component of the peroxisomal import pore. Here, we demonstrate that the membrane-associated import receptor Pex5p together with its docking partner Pex14p forms a gated ion-conducting channel which can be opened to a diameter of about 9 nm by the cytosolic receptor-cargo complex. The newly identified pore shows striking dynamics, as expected for an import machinery translocating proteins of variable sizes.
MeSH Terms
Acyl-CoA Oxidase/metabolism
Carrier Proteins/genetics
Electrophysiological Phenomena/physiology
Gene Deletion
Ion Channel Gating/physiology
Ion Channels/physiology
Membrane Potentials/physiology
Membrane Proteins/analysis,physiology
Membrane Transport Proteins/analysis,physiology
Membranes, Artificial
Models, Biological
Multiprotein Complexes/chemistry,isolation & purification,physiology
Peroxins
Peroxisome-Targeting Signal 1 Receptor
Peroxisomes/physiology
Porins/analysis,physiology
Protein Transport/physiology
Receptors, Cytoplasmic and Nuclear/analysis,physiology
Repressor Proteins/analysis,physiology
Saccharomyces cerevisiae/chemistry,physiology
Saccharomyces cerevisiae Proteins/analysis,genetics,metabolism,physiology
Ubiquitin-Protein Ligases/analysis,physiology
Unilamellar Liposomes/chemistry
Chemicals
Carrier Proteins
Ion Channels
Membrane Proteins
Membrane Transport Proteins
Membranes, Artificial
Multiprotein Complexes
PEX10 protein, S cerevisiae
PEX12 protein, S cerevisiae
PEX13 protein, S cerevisiae
PEX14 protein, S cerevisiae
PEX17 protein, S cerevisiae
PEX18 protein, S cerevisiae
PEX21 protein, S cerevisiae
PEX5 protein, S cerevisiae
Peroxins
Peroxisome-Targeting Signal 1 Receptor
Pex8 protein, S cerevisiae
Porins
Receptors, Cytoplasmic and Nuclear
Repressor Proteins
Saccharomyces cerevisiae Proteins
Unilamellar Liposomes
Acyl-CoA Oxidase
POX1 protein, S cerevisiae
Ubiquitin-Protein Ligases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Meinecke Michael
Biophysik, FB Biologie/Chemie, Universität Osnabrück, Germany.
Cizmowski Christian
Schliebs Wolfgang
Krüger Vivien
Beck Sabrina
Wagner Richard
Erdmann Ralf
References (32)
32 references, click to expand
-
Opinion: peroxisomal-protein import: is it really that complex?
Nat Rev Mol Cell Biol. 2002 May;3(5):382-9
PMID: 11988772
-
PTS2 co-receptors: diverse proteins with common features.
Biochim Biophys Acta. 2006 Dec;1763(12):1605-12
PMID: 17028014
-
Pex8p, an intraperoxisomal peroxin of Saccharomyces cerevisiae required for protein transport into peroxisomes binds the PTS1 receptor pex5p.
J Biol Chem. 2000 Feb 4;275(5):3593-602
PMID: 10652355
-
Protein translocons: multifunctional mediators of protein translocation across membranes.
Cell. 2003 Feb 21;112(4):491-505
PMID: 12600313
-
Tim50 maintains the permeability barrier of the mitochondrial inner membrane.
Science. 2006 Jun 9;312(5779):1523-6
PMID: 16763150
-
Ubiquitination of the peroxisomal import receptor Pex5p is required for its recycling.
J Cell Biol. 2007 Apr 23;177(2):197-204
PMID: 17452527
-
Peroxisomal dynamics.
Trends Cell Biol. 2007 Oct;17(10):474-84
PMID: 17913497
-
Protein insertion into the mitochondrial inner membrane by a twin-pore translocase.
Science. 2003 Mar 14;299(5613):1747-51
PMID: 12637749
-
Overproduction of Pex5p stimulates import of alcohol oxidase and dihydroxyacetone synthase in a Hansenula polymorpha Pex14 null mutant.
J Biol Chem. 2000 Apr 28;275(17):12603-11
PMID: 10777551
-
Pex14p, more than just a docking protein.
Biochim Biophys Acta. 2006 Dec;1763(12):1574-84
PMID: 17046076
-
Membrane association of the cycling peroxisome import receptor Pex5p.
J Biol Chem. 2006 Sep 15;281(37):27003-15
PMID: 16849337
-
Shuttling mechanism of peroxisome targeting signal type 1 receptor Pex5: ATP-independent import and ATP-dependent export.
Mol Cell Biol. 2005 Dec;25(24):10822-32
PMID: 16314507
-
Large cation-selective pores from rat liver peroxisomal membranes incorporated to planar lipid bilayers.
J Membr Biol. 1986;94(3):285-91
PMID: 2435912
-
Motor-free mitochondrial presequence translocase drives membrane integration of preproteins.
Nat Cell Biol. 2007 Oct;9(10):1152-9
PMID: 17828250
-
The N-terminal half of the peroxisomal cycling receptor Pex5p is a natively unfolded domain.
J Mol Biol. 2006 Mar 3;356(4):864-75
PMID: 16403517
-
The Sec61p complex is a dynamic precursor activated channel.
Mol Cell. 2003 Jul;12(1):261-8
PMID: 12887911
-
Analysis of the carboxyl-terminal peroxisomal targeting signal 1 in a homologous context in Saccharomyces cerevisiae.
J Biol Chem. 1996 Oct 18;271(42):26375-82
PMID: 8824293
-
Acyl-CoA oxidase is imported as a heteropentameric, cofactor-containing complex into peroxisomes of Yarrowia lipolytica.
J Cell Biol. 2002 Feb 4;156(3):481-94
PMID: 11815635
-
Reconstitution of a chloroplast protein import channel.
EMBO J. 1997 Dec 15;16(24):7351-60
PMID: 9405364
-
Tim22, the essential core of the mitochondrial protein insertion complex, forms a voltage-activated and signal-gated channel.
Mol Cell. 2002 Feb;9(2):363-73
PMID: 11864609
-
The preprotein conducting channel at the inner envelope membrane of plastids.
EMBO J. 2002 Jun 3;21(11):2616-25
PMID: 12032074
-
Peroxisomal targeting of PTS2 pre-import complexes in the yeast Saccharomyces cerevisiae.
Traffic. 2009 Apr;10(4):451-60
PMID: 19183303
-
Functional role of the AAA peroxins in dislocation of the cycling PTS1 receptor back to the cytosol.
Nat Cell Biol. 2005 Aug;7(8):817-22
PMID: 16007078
-
Peroxisomal matrix protein import: the transient pore model.
Nat Rev Mol Cell Biol. 2005 Sep;6(9):738-42
PMID: 16103872
-
Recognition of a functional peroxisome type 1 target by the dynamic import receptor pex5p.
Mol Cell. 2006 Dec 8;24(5):653-663
PMID: 17157249
-
Tom40 forms the hydrophilic channel of the mitochondrial import pore for preproteins [see comment].
Nature. 1998 Oct 1;395(6701):516-21
PMID: 9774109
-
A novel method for structure-based prediction of ion channel conductance properties.
Biophys J. 1997 Mar;72(3):1109-26
PMID: 9138559
-
Pex8p: an intraperoxisomal organizer of the peroxisomal import machinery.
Mol Cell. 2003 Mar;11(3):635-46
PMID: 12667447
-
Single-channel analysis of a large conductance channel in peroxisomes from rat liver.
Biochim Biophys Acta. 1989 Sep 18;984(3):351-9
PMID: 2476185
-
Import of stably folded proteins into peroxisomes.
Mol Biol Cell. 1995 Jun;6(6):675-83
PMID: 7579687
-
Characterization of peroxisomal Pex5p from rat liver. Pex5p in the Pex5p-Pex14p membrane complex is a transmembrane protein.
J Biol Chem. 2000 Oct 20;275(42):32444-51
PMID: 10889202
-
Translocation of proteins into mitochondria.
Annu Rev Biochem. 2007;76:723-49
PMID: 17263664