Signal-anchor sequences are an essential factor for the Golgi-plasma membrane localization of type II membrane proteins

ABSTRACT Despite studies of the mechanism underlying the intracellular localization of membrane proteins, the specific mechanisms by which each membrane protein localizes to the endoplasmic reticulum, Golgi apparatus, and plasma membrane in the secretory pathway are unclear. In this study, a discriminant analysis of endoplasmic reticulum, Golgi apparatus and plasma membrane-localized type II membrane proteins was performed using a position-specific scoring matrix derived from the amino acid propensity of the sequences around signal-anchors. The possibility that the sequence around the signal-anchor is a factor for identifying each localization group was evaluated. The discrimination accuracy between the Golgi apparatus and plasma membrane-localized type II membrane proteins was as high as 90%, indicating that, in addition to other factors, the sequence around signal-anchor is an essential component of the selection mechanism for the Golgi and plasma membrane localization. These results may improve the use of membrane proteins for drug delivery and therapeutic applications. GRAPHICAL ABSTRACT The sequence around the signal-anchor is an essential component of the selection mechanism for Golgi and plasma membrane protein localization.

[1]  G. Blobel,et al.  Protein translocation across the endoplasmic reticulum. , 1994, Current opinion in cell biology.

[2]  L. Orci,et al.  Clathrin-immunoreactive sites in the Golgi apparatus are concentrated at the trans pole in polypeptide hormone-secreting cells. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. Bonifacino,et al.  Colocalized transmembrane determinants for ER degradation and subunit assembly explain the intracellular fate of TCR chains , 1990, Cell.

[4]  M. Neuberger,et al.  The sequence of the mu transmembrane segment determines the tissue specificity of the transport of immunoglobulin M to the cell surface , 1990, The Journal of experimental medicine.

[5]  C. Machamer,et al.  A Golgi retention signal in a membrane-spanning domain of coronavirus E1 protein , 1991, The Journal of cell biology.

[6]  P. V. Balaji,et al.  Mutational analysis of the Golgi retention signal of bovine beta-1,4-galactosyltransferase. , 1993, The Journal of biological chemistry.

[7]  M. Robinson,et al.  The role of clathrin, adaptors and dynamin in endocytosis. , 1994, Current opinion in cell biology.

[8]  Jean-Michel Claverie,et al.  The statistical significance of nucleotide position-weight matrix matches , 1996, Comput. Appl. Biosci..

[9]  B. Jungnickel,et al.  Approaching the mechanism of protein transport across the ER membrane. , 1996, Current Opinion in Cell Biology.

[10]  J. Rothman,et al.  Sorting Determinants in the Transmembrane Domain of p24 Proteins* , 1997, The Journal of Biological Chemistry.

[11]  J. Ellenberg,et al.  The Transmembrane Domain of a Carboxyl-terminal Anchored Protein Determines Localization to the Endoplasmic Reticulum* , 1997, The Journal of Biological Chemistry.

[12]  L. Zaliauskiene,et al.  Down-regulation of cell surface receptors is modulated by polar residues within the transmembrane domain. , 2000, Molecular biology of the cell.

[13]  J. Bonifacino,et al.  Signals for sorting of transmembrane proteins to endosomes and lysosomes. , 2003, Annual review of biochemistry.

[14]  Jenn-Kang Hwang,et al.  Prediction of protein subcellular localization , 2006, Proteins.

[15]  Oliver Kohlbacher,et al.  MultiLoc: prediction of protein subcellular localization using N-terminal targeting sequences, sequence motifs and amino acid composition , 2006, Bioinform..

[16]  Paul Horton,et al.  Nucleic Acids Research Advance Access published May 21, 2007 WoLF PSORT: protein localization predictor , 2007 .

[17]  Hagit Shatkay,et al.  SherLoc: high-accuracy prediction of protein subcellular localization by integrating text and protein sequence data. , 2007, Bioinformatics.

[18]  S. Brunak,et al.  Locating proteins in the cell using TargetP, SignalP and related tools , 2007, Nature Protocols.

[19]  Oliver Kohlbacher,et al.  MultiLoc2: integrating phylogeny and Gene Ontology terms improves subcellular protein localization prediction , 2009, BMC Bioinformatics.

[20]  Hagit Shatkay,et al.  SherLoc2: a high-accuracy hybrid method for predicting subcellular localization of proteins. , 2009, Journal of proteome research.

[21]  L. Orci,et al.  Transmembrane domains control exclusion of membrane proteins from clathrin-coated pits , 2010, Journal of Cell Science.

[22]  Oliver Kohlbacher,et al.  YLoc—an interpretable web server for predicting subcellular localization , 2010, Nucleic Acids Res..

[23]  S. Munro,et al.  A Comprehensive Comparison of Transmembrane Domains Reveals Organelle-Specific Properties , 2010, Cell.

[24]  K. Chou,et al.  iLoc-Euk: A Multi-Label Classifier for Predicting the Subcellular Localization of Singleplex and Multiplex Eukaryotic Proteins , 2011, PloS one.

[25]  P. Gleeson,et al.  Rab9-dependent retrograde transport and endosomal sorting of the endopeptidase furin , 2011, Journal of Cell Science.

[26]  T. Hirokawa,et al.  Discrimination of Golgi Type II Membrane Proteins Based on Their Hydropathy Profiles and the Amino Acid Propensities of Their Transmembrane Regions , 2011, Bioscience, biotechnology, and biochemistry.

[27]  R. Cummings,et al.  The Transmembrane Domain of the Molecular Chaperone Cosmc Directs Its Localization to the Endoplasmic Reticulum* , 2011, The Journal of Biological Chemistry.

[28]  Longbo Hu,et al.  The Golgi Localization of GOLPH2 (GP73/GOLM1) Is Determined by the Transmembrane and Cytoplamic Sequences , 2011, PloS one.

[29]  Mazen Ahmad,et al.  Protein translocation across the ER membrane. , 2011, Biochimica et biophysica acta.

[30]  Zhengwei Zhu,et al.  CD-HIT: accelerated for clustering the next-generation sequencing data , 2012, Bioinform..

[31]  Burkhard Rost,et al.  Supporting online material for : LocTree 2 predicts localization for all domains of life , 2012 .

[32]  J. Bonifacino,et al.  Anchors aweigh: protein localization and transport mediated by transmembrane domains , 2013, Trends in Cell Biology.

[33]  R. Schekman,et al.  Copii — a Flexible Vesicle Formation System This Review Comes from a Themed Issue on Cell Organelles Biophysics of Copii-mediated Vesicle Formation , 2022 .

[34]  Burkhard Rost,et al.  LocTree3 prediction of localization , 2014, Nucleic Acids Res..

[35]  Arne Elofsson,et al.  The TOPCONS web server for consensus prediction of membrane protein topology and signal peptides , 2015, Nucleic Acids Res..

[36]  Michele Magrane,et al.  Searching and Navigating UniProt Databases , 2015, Current protocols in bioinformatics.

[37]  Shibiao Wan,et al.  Machine Learning for Protein Subcellular Localization Prediction , 2015 .

[38]  Ole Winther,et al.  DeepLoc: prediction of protein subcellular localization using deep learning , 2017, Bioinform..

[39]  R. Zimmermann,et al.  Let’s talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine , 2017, Signal Transduction and Targeted Therapy.