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Chapter 5 the Mammalian Retromer Complex: 139 PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/77567 Please be advised that this information was generated on 2021-09-29 and may be subject to change. The Role of the Retromer Complex in Receptor Trafficking The Role of the Retromer Complex in Receptor Trafficking Een wetenschappelijke proeve op het gebied van de Natuurwetenschappen, Wiskunde en Informatica Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. mr. S.C.J.J. Kortmann, volgens besluit van het College van Decanen in het openbaar te verdedigen op maandag 05 juli 2010 om 13.30 uur precies door Ester Damen geboren op 03 maart 1981 te Dongen Promotor: Prof. dr. E. J. J. van Zoelen Copromotor: Dr. J. E. M. van Leeuwen Manuscriptcommissie: Prof. dr. B. Wieringa Dr. P. M. T. Deen Prof. dr. J. Klumperman; University of Utrecht ISBN: 978-90-9025409-8 Print: Ipskamp Drukkers, Enschede Cover: Designed by Ton Dirks hVps29 amino acid sequence; molecular model of the hVps29 active site; model of retromer mediated transport The research presented in this thesis was performed at the Department of Cell Biology, Faculty of Science at the Radboud University Nijmegen. The studies were supported financially by Zon-MW (908-02-047). Table of Contents Chapter 1 General Introduction 7 1.1 Intracellular compartments and transport 1.2 Receptor trafficking 1.3 Yeast sorting nexin/retromer complex 1.4 Mammalian sorting nexin/retromer complex 1.5 Thesis outline Chapter 2 Fold recognition predicts similarity of retromer subunits 63 Vps26, Vps29 and Vps35 with ß-arrestins, metallo- phosphoesterases and ARM/HEAT repeat solenoid proteins, respectively Chapter 3 Phylogenetic analysis of retromer subunits 85 Chapter 4 The human Vps29 retromer component is a metallo- 107 phosphoesterase for a cation-independent mannose 6- phosphate receptor substrate peptide Chapter 5 The mammalian retromer complex: 139 An adaptor between cargo and microtubule tracks? Chapter 6 Extensive study of epitope-tagged expression of wild-type and 163 mutant retromer proteins Chapter 7 ErbB2 and ErbB4 Cbl binding sites can functionally replace the 187 ErbB1 Cbl binding site Chapter 8 General Discussion 209 8.1 Structure of retromer subunits 8.2 Assembly of the sorting nexin/retromer complex 8.3 The sorting nexin/retromer complex as vesicular coat complex 8.4 The retromer complex and endosome-to-Golgi retrieval pathways 8.5 Retromer complex and cargo selection 8.6 The role of sorting nexin/retromer complex in disease Summary 233 Samenvatting 237 Dankwoord 241 Curriculum Vitae 245 Publications 245 Chapter 1 General Introduction 8 Chapter 1 1.1 Intracellular Compartments and Transport Bacteria, archaea and eukaryotes form the three kingdoms of life. The latter group includes protists, fungi, plants and animals. Compared to bacteria and archaea, eukaryotic cells are highly complex systems that are characterized by the presence of a nucleus, various membrane-enclosed compartments (organelles) and the presence of cytoskeletal structures including microfilaments, intermediate filaments and microtubules. The presence of specialized organelles provides the eukaryotic cell with the ability to compartmentalize many different intracellular processes with specific vital functions. For instance, mitochondria take care of the energy metabolism, peroxisomes function in fatty acid oxidation and neutralization of reactive oxygen species while the cell nucleus is the place of DNA storage, transcription and ribosomal RNA synthesis. Eukaryotes also contain an elaborate endomembrane system composed of various organelles including the endoplasmic reticulum (ER), Golgi apparatus, endosomes and lysosomes. The Golgi apparatus receives proteins made in the ER and functions in the modification, sorting and packaging of these proteins for either plasma membrane targeting, secretion or delivery to endosomes or lysosomes. Lysosomes are responsible for the intracellular degradation of endocytosed material. Due to the subcellular compartmentalization strategy, the eukaryotic cell also contains elaborate pathways to ensure proper targeting of proteins to various organelles and membranes. While specific protein sorting pathways exist to target proteins to mitochondria, peroxisomes and the nucleus, proteins that are destined for the endomembrane system are targeted to the rough ER. Communication and transport between organelles of the endomembrane system occurs via (tubulo-)vesicular transport intermediates that move along microtubule tracks from one place in the cell to another. In this thesis we focus on a protein complex called retromer, which is essential in vesicular endosome-to-Golgi transport, and functions in a very unique manner, due to its protein composition and interplay. Secretory Pathway Intracellular traffic occurs mainly via two routes: the outward biosynthetic secretory pathway and the inward endocytic pathway. Both pathways are interconnected and therefore endosomes are not only key players in the endosomal pathway, but also in the sorting of proteins in the biosynthetic secretory route (Figure 1). The secretory pathway is mainly used by newly synthesized proteins. Proteins are translated on ribosomes bound to the ER and co-translationally imported or inserted in the ER membrane. In the ER, N- glycosylation and disulfide bond formation can take place. Once these proteins are properly General Introduction 9 folded and assembled they are transported from the ER to the cis face of the Golgi apparatus, probably via maturation of an ER-Golgi intermediate compartment (ERGIC), which fuses with the Golgi to generate new Golgi cisternae (reviewed by [1, 2]). The Golgi has a peri-nuclear localization and consists of flattened cisternae, classified into cis, medial or trans cisternae where N-glycan processing and O-glycosylation takes place. By maturation of the Golgi, proteins reach the last station of the secretory pathway, the trans-Golgi network (TGN) (reviewed by [3, 4]). In the TGN soluble and membrane proteins are packaged into distinct transport intermediates and subsequently delivered to their destination: the plasma membrane, secretory granules, or endocytic/lysosomal compartments (reviewed by [5, 6]). Figure 1 Intracellular transport pathways. The scheme depicts the compartments of the outward biosynthetic secretory pathway and the inward endocytic pathway. Transport steps are indicated by arrows. Colours indicate the known or presumed locations of the coat proteins COPII (blue), COPI (red), and clathrin (orange). Additional coats or coat-like complexes exist, but are not represented in this figure [23]. Endocytic Pathway The endosomal system is a major membrane-sorting apparatus for receptors and other plasma membrane proteins internalized from the cell surface. Understanding the details of the complex and interconnected endocytic trafficking pathways that can carry molecules within the endosomal system, is essential for analyzing many crucial cellular processes such as cell growth and cell signaling, immunity and viral infection, toxicity, nutrient uptake, and many other fundamental cell biological processes. The endosomal sorting starts at the plasma membrane of the cell. There are several mechanisms for internalizing molecules from the cell surface, including phagocytosis, caveolae formation, membrane ruffling, (non-) clathrin-coated pit formation and STEM (surface-connected tubules entering macrophages) 10 Chapter 1 formation [7]. From these different forms of endocytosis, receptor-mediated endocytosis is the best understood process and involves the internalization of ligand-bound receptors by clathrin-coated pits (reviewed by [8]). After removal of their clathrin coats, the newly formed endosomal vesicles can dock and fuse with each other to form sorting endosomes. Sorting endosomes, also referred to as early endosomes, are compartments located to the periphery of the cell with a tubular-vesicular structure and a luminal pH of ~6.0. As a consequence of this low pH, many ligands are released from their receptors. The main function of the sorting endosome is the targeting of proteins to their correct location. The predominant sorting in the sorting endosome is not based on the recognition of a specific sorting motif in the cargo proteins, but is based on organelle geometry. Up to 80% of the membrane surface area of sorting endosomes is present in tubules that bud out from the sorting endosome [9, 10] and carry with them a large fraction of membrane components. Many membrane components are recycled directly from the sorting endosome to the plasma membrane, while other components use an indirect pathway, which involves recycling via the endocytic recycling compartment (ERC). The preference for one of the pathways is likely to be dependent on specific sorting signals that are still unidentified, but that are necessary for the sorting of proteins into another compartment than the default pathway. A large fraction of membrane proteins pass through the ERC, which is mainly composed of narrow diameter tubules that are associated with microtubules [11-13]. In some cell types, the ERC is localized close to the microtubule-organizing centre (MTOC) [14]. The ERC can sort proteins to several destinations, whereby most molecules are returned to the plasma membrane and a minor fraction is sorted to the
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