PMID- 10069808
OWN - NLM
STAT- MEDLINE
DCOM- 19990401
LR  - 20181201
IS  - 1059-1524 (Print)
IS  - 1059-1524 (Linking)
VI  - 10
IP  - 3
DP  - 1999 Mar
TI  - MCD4 encodes a conserved endoplasmic reticulum membrane protein essential for
      glycosylphosphatidylinositol anchor synthesis in yeast.
PG  - 627-48
AB  - 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.
FAU - Gaynor, E C
AU  - Gaynor EC
AD  - Department of Biology, The Division of Cellular and Molecular Medicine,
      University of California, San Diego, La Jolla, California 92093-0668, USA.
FAU - Mondesert, G
AU  - Mondesert G
FAU - Grimme, S J
AU  - Grimme SJ
FAU - Reed, S I
AU  - Reed SI
FAU - Orlean, P
AU  - Orlean P
FAU - Emr, S D
AU  - Emr SD
LA  - eng
SI  - GENBANK/AF109219
GR  - R01 GM038328/GM/NIGMS NIH HHS/United States
GR  - CA-58689/CA/NCI NIH HHS/United States
GR  - R37 GM038328/GM/NIGMS NIH HHS/United States
GR  - R01 GM046220/GM/NIGMS NIH HHS/United States
GR  - GM-46220/GM/NIGMS NIH HHS/United States
GR  - GM-38328/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Biol Cell
JT  - Molecular biology of the cell
JID - 9201390
RN  - 0 (Ethanolamines)
RN  - 0 (Fungal Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Glycosphingolipids)
RN  - 0 (Glycosylphosphatidylinositols)
RN  - 0 (HSP150 protein, S cerevisiae)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (MCD4 protein, S cerevisiae)
RN  - 0 (Membrane Proteins)
RN  - 0 (PEP1 protein, S cerevisiae)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Saccharomyces cerevisiae Proteins)
RN  - 0 (Vesicular Transport Proteins)
RN  - 0 (inositolphosphoceramides)
RN  - 78A2BX7AEU (phosphorylethanolamine)
SB  - IM
MH  - Amino Acid Sequence
MH  - Biological Transport
MH  - Conserved Sequence
MH  - Endoplasmic Reticulum/*metabolism
MH  - Ethanolamines/chemistry/metabolism
MH  - Fungal Proteins/*genetics/metabolism
MH  - *Glycoproteins
MH  - Glycosphingolipids/metabolism
MH  - Glycosylation
MH  - Glycosylphosphatidylinositols/*biosynthesis
MH  - Golgi Apparatus/metabolism
MH  - Heat-Shock Proteins/metabolism
MH  - Humans
MH  - Intracellular Membranes/chemistry/metabolism
MH  - Membrane Proteins/*genetics/*metabolism
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Receptors, Cell Surface/metabolism
MH  - Saccharomyces cerevisiae/*physiology
MH  - *Saccharomyces cerevisiae Proteins
MH  - Schizosaccharomyces/genetics/metabolism
MH  - Sequence Homology, Amino Acid
MH  - *Vesicular Transport Proteins
PMC - PMC25192
EDAT- 1999/03/09 00:00
MHDA- 1999/03/09 00:01
CRDT- 1999/03/09 00:00
PHST- 1999/03/09 00:00 [pubmed]
PHST- 1999/03/09 00:01 [medline]
PHST- 1999/03/09 00:00 [entrez]
AID - 10.1091/mbc.10.3.627 [doi]
PST - ppublish
SO  - Mol Biol Cell. 1999 Mar;10(3):627-48. doi: 10.1091/mbc.10.3.627.