![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 10, Issue 3, 627-648, March 1999
§
*Department of Biology, The Division of Cellular and Molecular
Medicine, and the Howard Hughes Medical Institute, University of
California, San Diego, La Jolla, California 92093-0668;
§The Scripps Research Institute, Department of Molecular
Biology, La Jolla, California 92037; and ¶Department of
Biochemistry, University of Illinois at Urbana-Champaign, Urbana,
Illinois 61801
Glycosylphosphatidylinositol
(GPI)-anchored proteins are cell surface-localized proteins that serve
many important cellular functions. The pathway mediating synthesis and
attachment of the GPI anchor to these proteins in eukaryotic cells is
complex, highly conserved, and plays a critical role in the proper
targeting, transport, and function of all GPI-anchored protein family
members. In this article, we demonstrate that MCD4, an
essential gene that was initially identified in a genetic screen to
isolate Saccharomyces cerevisiae mutants defective for
bud emergence, encodes a previously unidentified component of the GPI
anchor synthesis pathway. Mcd4p is a multimembrane-spanning protein
that localizes to the endoplasmic reticulum (ER) and contains a large
NH2-terminal ER lumenal domain. We have also cloned the
human MCD4 gene and found that Mcd4p is both highly
conserved throughout eukaryotes and has two yeast homologues. Mcd4p's
lumenal domain contains three conserved motifs found in mammalian
phosphodiesterases and nucleotide pyrophosphases; notably, the
temperature-conditional MCD4 allele used for our studies
(mcd4-174) harbors a single amino acid change in motif 2. The mcd4-174 mutant (1) is defective in ER-to-Golgi
transport of GPI-anchored proteins (i.e., Gas1p) while other proteins
(i.e., CPY) are unaffected; (2) secretes and releases (potentially
up-regulated cell wall) proteins into the medium, suggesting a defect
in cell wall integrity; and (3) exhibits marked morphological defects, most notably the accumulation of distorted, ER- and vesicle-like membranes. mcd4-174 cells synthesize all classes of
inositolphosphoceramides, indicating that the GPI protein
transport block is not due to deficient ceramide synthesis. However,
mcd4-174 cells have a severe defect in incorporation of
[3H]inositol into proteins and accumulate several
previously uncharacterized [3H]inositol-labeled
lipids whose properties are consistent with their being GPI precursors.
Together, these studies demonstrate that MCD4 encodes a
new, conserved component of the GPI anchor synthesis pathway and
highlight the intimate connections between GPI anchoring, bud
emergence, cell wall function, and feedback mechanisms likely to be
involved in regulating each of these essential processes. A putative
role for Mcd4p as participating in the modification of GPI anchors with
side chain phosphoethanolamine is also discussed.
These authors contributed equally to
this work.
Department of Microbiology
and Immunology, Stanford University School of Medicine, Fairchild
Building, Room D051, 299 Campus Drive,
Stanford, CA 94305-5124;
Microcide Phar-maceuticals
Inc., 850 Maude Avenue, Mountain View, CA 94043.
This article has been cited by other articles:
|
|
 |
|
  P. Orlean and A. K. Menon Thematic review series: Lipid Posttranslational Modifications. GPI anchoring of protein in yeast and mammalian cells, or: how we learned to stop worrying and love glycophospholipids J. Lipid Res., May 1, 2007; 48(5): 993 - 1011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Vainauskas and A. K. Menon Ethanolamine Phosphate Linked to the First Mannose Residue of Glycosylphosphatidylinositol (GPI) Lipids Is a Major Feature of the GPI Structure That Is Recognized by Human GPI Transamidase J. Biol. Chem., December 15, 2006; 281(50): 38358 - 38364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhu, C. Vionnet, and A. Conzelmann Ethanolaminephosphate Side Chain Added to Glycosylphosphatidylinositol (GPI) Anchor by Mcd4p Is Required for Ceramide Remodeling and Forward Transport of GPI Proteins from Endoplasmic Reticulum to Golgi J. Biol. Chem., July 21, 2006; 281(29): 19830 - 19839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Kersting and G. M. Carman Regulation of the Saccharomyces cerevisiae EKI1-encoded Ethanolamine Kinase by Zinc Depletion J. Biol. Chem., May 12, 2006; 281(19): 13110 - 13116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Bowman, A. Piwowar, M. Al Dabbous, J. Vierula, and S. J. Free Mutational Analysis of the Glycosylphosphatidylinositol (GPI) Anchor Pathway Demonstrates that GPI-Anchored Proteins Are Required for Cell Wall Biogenesis and Normal Hyphal Growth in Neurospora crassa Eukaryot. Cell, March 1, 2006; 5(3): 587 - 600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shishioh, Y. Hong, K. Ohishi, H. Ashida, Y. Maeda, and T. Kinoshita GPI7 Is the Second Partner of PIG-F and Involved in Modification of Glycosylphosphatidylinositol J. Biol. Chem., March 11, 2005; 280(10): 9728 - 9734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fujita, T. Yoko-o, M. Okamoto, and Y. Jigami GPI7 Involved in Glycosylphosphatidylinositol Biosynthesis Is Essential for Yeast Cell Separation J. Biol. Chem., December 10, 2004; 279(50): 51869 - 51879. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kipnis, N. Thomas, R. Ovalle, and P. N. Lipke The ER-Golgi v-SNARE Bet1p is required for cross-linking {alpha}-agglutinin to the cell wall in yeast Microbiology, October 1, 2004; 150(10): 3219 - 3228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Ellis, F. Wang, C. W. MacDiarmid, S. Clark, T. Lyons, and D. J. Eide Zinc and the Msc2 zinc transporter protein are required for endoplasmic reticulum function J. Cell Biol., August 2, 2004; 166(3): 325 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Grimme, X.-D. Gao, P. S. Martin, K. Tu, S. E. Tcheperegine, K. Corrado, A. E. Farewell, P. Orlean, and E. Bi Deficiencies in the Endoplasmic Reticulum (ER)-Membrane Protein Gab1p Perturb Transfer of Glycosylphosphatidylinositol to Proteins and Cause Perinuclear ER-associated Actin Bar Formation Mol. Biol. Cell, June 1, 2004; 15(6): 2758 - 2770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Imhof, I. Flury, C. Vionnet, C. Roubaty, D. Egger, and A. Conzelmann Glycosylphosphatidylinositol (GPI) Proteins of Saccharomyces cerevisiae Contain Ethanolamine Phosphate Groups on the {alpha}1,4-linked Mannose of the GPI Anchor J. Biol. Chem., May 7, 2004; 279(19): 19614 - 19627. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lalanne, D. Honys, A. Johnson, G. H. H. Borner, K. S. Lilley, P. Dupree, U. Grossniklaus, and D. Twell SETH1 and SETH2, Two Components of the Glycosylphosphatidylinositol Anchor Biosynthetic Pathway, Are Required for Pollen Germination and Tube Growth in Arabidopsis PLANT CELL, January 1, 2004; 16(1): 229 - 240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhong, R. Malhotra, and G. Guidotti ATP Uptake in the Golgi and Extracellular Release Require Mcd4 Protein and the Vacuolar H+-ATPase J. Biol. Chem., August 29, 2003; 278(35): 33436 - 33444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Cowart, Y. Okamoto, F. R. Pinto, J. L. Gandy, J. S. Almeida, and Y. A. Hannun Roles for Sphingolipid Biosynthesis in Mediation of Specific Programs of the Heat Stress Response Determined through Gene Expression Profiling J. Biol. Chem., August 8, 2003; 278(32): 30328 - 30338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Umemura, M. Okamoto, K.-i. Nakayama, K. Sagane, K. Tsukahara, K. Hata, and Y. Jigami GWT1 Gene Is Required for Inositol Acylation of Glycosylphosphatidylinositol Anchors in Yeast J. Biol. Chem., June 20, 2003; 278(26): 23639 - 23647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Delorenzi, A. Sexton, H. Shams-Eldin, R. T. Schwarz, T. Speed, and L. Schofield Genes for Glycosylphosphatidylinositol Toxin Biosynthesis in Plasmodium falciparum Infect. Immun., August 1, 2002; 70(8): 4510 - 4522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Storey, K. L. Clay, T. Kutateladze, R. C. Murphy, M. Overduin, and D. R. Voelker Phosphatidylethanolamine Has an Essential Role in Saccharomyces cerevisiae That Is Independent of Its Ability to Form Hexagonal Phase Structures J. Biol. Chem., December 14, 2001; 276(51): 48539 - 48548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Fraering, I. Imhof, U. Meyer, J.-M. Strub, A. van Dorsselaer, C. Vionnet, and A. Conzelmann The GPI Transamidase Complex of Saccharomyces cerevisiae Contains Gaa1p, Gpi8p, and Gpi16p Mol. Biol. Cell, October 1, 2001; 12(10): 3295 - 3306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Vai, L. Brambilla, I. Orlandi, N. Rota, B. M. Ranzi, L. Alberghina, and D. Porro Improved Secretion of Native Human Insulin-Like Growth Factor 1 from gas1 Mutant Saccharomyces cerevisiae Cells Appl. Envir. Microbiol., December 1, 2000; 66(12): 5477 - 5479. [Abstract] [Full Text]
|
|
|
|
 |
|
 I. Imhof, E. Canivenc-Gansel, U. Meyer, and A. Conzelmann Phosphatidylethanolamine is the donor of the phosphorylethanolamine linked to the {{alpha}}1,4-linked mannose of yeast GPI structures Glycobiology, December 1, 2000; 10(12): 1271 - 1275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Yuan Zinc-Regulated Genes in Saccharomyces cerevisiae Revealed by Transposon Tagging Genetics, September 1, 2000; 156(1): 45 - 58. [Abstract] [Full Text]
|
|
|
|
|
|
C. H. Taron, J. M. Wiedman, S. J. Grimme, and P. Orlean Glycosylphosphatidylinositol Biosynthesis Defects in Gpi11p- and Gpi13p-deficient Yeast Suggest a Branched Pathway and Implicate Gpi13p in Phosphoethanolamine Transfer to the Third Mannose Mol. Biol. Cell, May 1, 2000; 11(5): 1611 - 1630. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Hong, Y. Maeda, R. Watanabe, K. Ohishi, M. Mishkind, H. Riezman, and T. Kinoshita Pig-n, a Mammalian Homologue of Yeast Mcd4p, Is Involved in Transferring Phosphoethanolamine to the First Mannose of the Glycosylphosphatidylinositol J. Biol. Chem., December 3, 1999; 274(49): 35099 - 35106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hong, Y. Maeda, R. Watanabe, N. Inoue, K. Ohishi, and T. Kinoshita Requirement of PIG-F and PIG-O for Transferring Phosphoethanolamine to the Third Mannose in Glycosylphosphatidylinositol J. Biol. Chem., June 30, 2000; 275(27): 20911 - 20919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Flury, A. Benachour, and A. Conzelmann YLL031c Belongs to a Novel Family of Membrane Proteins Involved in the Transfer of Ethanolaminephosphate onto the Core Structure of Glycosylphosphatidylinositol Anchors in Yeast J. Biol. Chem., August 4, 2000; 275(32): 24458 - 24465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yada, R. Sugiura, A. Kita, Y. Itoh, Y. Lu, Y. Hong, T. Kinoshita, H. Shuntoh, and T. Kuno Its8, a Fission Yeast Homolog of Mcd4 and Pig-n, Is Involved in GPI Anchor Synthesis and Shares an Essential Function with Calcineurin in Cytokinesis J. Biol. Chem., April 20, 2001; 276(17): 13579 - 13586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Grimme, B. A. Westfall, J. M. Wiedman, C. H. Taron, and P. Orlean The Essential Smp3 Protein Is Required for Addition of the Side-branching Fourth Mannose during Assembly of Yeast Glycosylphosphatidylinositols J. Biol. Chem., July 13, 2001; 276(29): 27731 - 27739. [Abstract] [Full Text] [PDF]
|
|
