PMID- 34186010
OWN - NLM
STAT- MEDLINE
DCOM- 20220202
LR  - 20221209
IS  - 2046-2441 (Electronic)
IS  - 2046-2441 (Linking)
VI  - 11
IP  - 6
DP  - 2021 Jun
TI  - Determination of the membrane topology of PORCN, an O-acyl transferase that 
      modifies Wnt signalling proteins.
PG  - 200400
LID - 10.1098/rsob.200400 [doi]
LID - 200400
AB  - Wnt gradients elicit distinct cellular responses, such as proliferation, 
      specification, differentiation and survival in a dose-dependent manner. Porcupine 
      (PORCN), a membrane-bound O-acyl transferase (MBOAT) that resides in the 
      endoplasmic reticulum, catalyses the addition of monounsaturated palmitate to Wnt 
      proteins and is required for Wnt gradient formation and signalling. In humans, 
      PORCN mutations are causal for focal dermal hypoplasia (FDH), an X-linked 
      dominant syndrome characterized by defects in mesodermal and endodermal tissues. 
      PORCN is also an emerging target for cancer therapeutics. Despite the importance 
      of this enzyme, its structure remains poorly understood. Recently, the crystal 
      structure of DltB, an MBOAT family member from bacteria, was solved. In this 
      report, we use experimental data along with homology modelling to DltB to 
      determine the membrane topology of PORCN. Our studies reveal that PORCN has 11 
      membrane domains, comprising nine transmembrane spanning domains and two 
      reentrant domains. The N-terminus is oriented towards the lumen while the 
      C-terminus is oriented towards the cytosol. Like DltB, PORCN has a funnel-like 
      structure that is encapsulated by multiple membrane-spanning helices. This new 
      model for PORCN topology allows us to map residues that are important for 
      biological activity (and implicated in FDH) onto its three-dimensional structure.
FAU - Galli, Lisa M
AU  - Galli LM
AD  - Department of Biology, San Francisco State University, 1600 Holloway Avenue, San 
      Francisco, CA 94132, USA.
FAU - Anderson, Marc O
AU  - Anderson MO
AD  - Department of Chemistry and Biochemistry, San Francisco State University, 1600 
      Holloway Avenue, San Francisco, CA 94132, USA.
FAU - Gabriel Fraley, J
AU  - Gabriel Fraley J
AD  - Department of Biology, San Francisco State University, 1600 Holloway Avenue, San 
      Francisco, CA 94132, USA.
FAU - Sanchez, Luis
AU  - Sanchez L
AD  - Department of Biology, San Francisco State University, 1600 Holloway Avenue, San 
      Francisco, CA 94132, USA.
FAU - Bueno, Raymund
AU  - Bueno R
AD  - Department of Biology, San Francisco State University, 1600 Holloway Avenue, San 
      Francisco, CA 94132, USA.
FAU - Hernandez, David N
AU  - Hernandez DN
AD  - Department of Biology, San Francisco State University, 1600 Holloway Avenue, San 
      Francisco, CA 94132, USA.
FAU - Maddox, Eva U
AU  - Maddox EU
AD  - Department of Biology, San Francisco State University, 1600 Holloway Avenue, San 
      Francisco, CA 94132, USA.
FAU - Lingappa, Vishwanath R
AU  - Lingappa VR
AD  - Prosetta Biosciences, 670 5th Street, San Francisco, CA 94107, USA.
FAU - Burrus, Laura W
AU  - Burrus LW
AD  - Department of Biology, San Francisco State University, 1600 Holloway Avenue, San 
      Francisco, CA 94132, USA.
LA  - eng
GR  - R25 GM059298/GM/NIGMS NIH HHS/United States
GR  - T34 GM008574/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210630
PL  - England
TA  - Open Biol
JT  - Open biology
JID - 101580419
RN  - 0 (Membrane Proteins)
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 2.3.1.- (PORCN protein, human)
SB  - IM
MH  - Acyltransferases/chemistry/*metabolism
MH  - Algorithms
MH  - Animals
MH  - Cell Line
MH  - Cell Membrane/*chemistry/*metabolism
MH  - Computational Biology/methods
MH  - Consensus Sequence
MH  - Fluorescent Antibody Technique
MH  - Glycosylation
MH  - Humans
MH  - Membrane Proteins/chemistry/*metabolism
MH  - Models, Molecular
MH  - Molecular Dynamics Simulation
MH  - Protein Binding
MH  - Protein Conformation
MH  - Structure-Activity Relationship
MH  - *Wnt Signaling Pathway
PMC - PMC8241489
OTO - NOTNLM
OT  - MBOAT
OT  - O-acyl transferase
OT  - Porcupine
OT  - Wnt
OT  - membrane topology
OT  - palmitoylation
EDAT- 2021/06/30 06:00
MHDA- 2022/02/03 06:00
PMCR- 2021/06/30
CRDT- 2021/06/29 20:09
PHST- 2021/06/29 20:09 [entrez]
PHST- 2021/06/30 06:00 [pubmed]
PHST- 2022/02/03 06:00 [medline]
PHST- 2021/06/30 00:00 [pmc-release]
AID - rsob200400 [pii]
AID - 10.1098/rsob.200400 [doi]
PST - ppublish
SO  - Open Biol. 2021 Jun;11(6):200400. doi: 10.1098/rsob.200400. Epub 2021 Jun 30.