Surf4 (Erv29p) binds amino-terminal tripeptide motifs of soluble cargo proteins with different affinities, enabling prioritization of their exit from the endoplasmic reticulum
| Autor: | Anna S. Nam, Mekka R. Garcia, Alexander J. Novak, Ying Yin, Raira S. Ank, Larry W. Fisher, Allison M. Saunders |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Peptide Hormones Amino Acid Motifs Vesicular Transport Proteins Tripeptide Plasma protein binding Endoplasmic Reticulum Biochemistry Database and Informatics Methods Cargo Proteins Biology (General) Secretory Pathway General Neuroscience Cell biology Transport protein Protein Transport Cell Processes COP-Coated Vesicles Cellular Structures and Organelles Signal transduction General Agricultural and Biological Sciences Oligopeptides Sequence Analysis Protein Binding Signal Transduction Research Article Saccharomyces cerevisiae Proteins Bioinformatics QH301-705.5 Saccharomyces cerevisiae Biology Research and Analysis Methods General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Sequence Motif Analysis Microsomes Humans Protein Interaction Domains and Motifs Vesicles Binding site Binding Sites 030102 biochemistry & molecular biology General Immunology and Microbiology Endoplasmic reticulum Genetic Complementation Test HEK 293 cells Membrane Proteins Biology and Life Sciences Proteins Cell Biology Hormones HEK293 Cells 030104 developmental biology Secretory protein Gene Expression Regulation Growth Hormone Cargo Receptors |
| Zdroj: | PLoS Biology, Vol 16, Iss 8, p e2005140 (2018) PLoS Biology |
| ISSN: | 1545-7885 |
| DOI: | 10.1371/journal.pbio.2005140 |
| Popis: | Some secreted proteins that assemble into large complexes, such as extracellular matrices or hormones and enzymes in storage granules, must be kept at subaggregation concentrations during intracellular trafficking. We show surfeit locus protein 4 (Surf4) is the cargo receptor that establishes different steady-state concentrations for a variety of soluble cargo proteins within the endoplasmic reticulum (ER) through interaction with the amino-terminal tripeptides exposed after removal of leader sequences. We call this motif the ER-Exit by Soluble Cargo using Amino-terminal Peptide-Encoding motif (ER-ESCAPE motif). Proteins that most readily aggregate in the ER lumen (e.g., dentin sialophosphoprotein [DSPP] and amelogenin, X-linked [AMELX]) have strong ER-ESCAPE motifs to inhibit aggregate formation, while less susceptible cargo exhibits weaker motifs. Specific changes in a single amino acid of the tripeptide result in aggregate formation and failure to efficiently traffic cargo out of the ER. A logical subset of 8,000 possible tripeptides starting a model soluble cargo protein (growth hormone) established a continuum of steady-state ER concentrations ranging from low (i.e., high affinity for receptor) to the highest concentrations associated with bulk flow–limited trafficking observed for nonbinding motifs. Human cells lacking Surf4 no longer preferentially trafficked cargo expressing strong ER-ESCAPE motifs. Reexpression of Surf4 or expression of yeast’s ortholog, ER-derived vesicles protein 29 (Erv29p), rescued enhanced ER trafficking in Surf4-null cells. Hence our work describes a new way of preferentially exporting soluble cargo out of the ER that maintains proteins below the concentrations at which they form damaging aggregates. Author summary The majority of proteins secreted from eukaryotic cells are targeted to the endoplasmic reticulum (ER) for folding and maturation and are then transferred by ER-exit vesicles to the Golgi for additional processing and eventual secretion from the plasma membrane. Large protein complexes such as those formed by extracellular matrices and hormones require that monomer concentrations in the ER remain low to inhibit polymerization or aggregation. For such cargo, diffusion into the lumen of ER-exit vesicles alone (bulk flow) is insufficient, and more efficient trafficking is required, necessitating binding to ER-exit vesicle transmembrane cargo receptors. We show that amino-terminal tripeptides of several secreted proteins bind to transmembrane cargo receptor, surfeit locus protein 4 (Surf4), for increased ER-trafficking efficiency. Yeast’s homolog, ER-derived vesicles protein 29 (Erv29p), is functionally conserved, as it could rescue efficient ER trafficking in Surf4-null human cells. Proteome database analyses of candidate secreted proteins and direct experimentation with representative cargo proteins uncovered a range of tripeptide compositions that confer high, modest, or low efficiency of ER trafficking. Furthermore, many soluble chaperone proteins that function within the ER—as well as proteins too large to enter classic coat protein complex II (COPII) ER-exit vesicles, such as fibrillar collagens—start with tripeptides that cannot bind to Surf4/Erv29p. When cargo concentrations exceeded Surf4 levels, trafficking of problematical proteins was prioritized by use of their higher affinity ER-Exit by Soluble Cargo using Amino-terminal Peptide-Encoding motifs (ER-ESCAPE motifs). |
| Databáze: | OpenAIRE |
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