PMID- 37852257
OWN - NLM
STAT- MEDLINE
DCOM- 20231114
LR  - 20240207
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Print)
IS  - 0092-8674 (Linking)
VI  - 186
IP  - 23
DP  - 2023 Nov 9
TI  - Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling.
PG  - 5028-5040.e14
LID - S0092-8674(23)01075-9 [pii]
LID - 10.1016/j.cell.2023.09.021 [doi]
AB  - Wnt proteins are enzymatically lipidated by Porcupine (PORCN) in the ER and bind 
      to Wntless (WLS) for intracellular transport and secretion. Mechanisms governing 
      the transfer of these low-solubility Wnts from the ER to the extracellular space 
      remain unclear. Through structural and functional analyses of Wnt7a, a crucial 
      Wnt involved in central nervous system angiogenesis and blood-brain barrier 
      maintenance, we have elucidated the principles of Wnt biogenesis and 
      Wnt7-specific signaling. The Wnt7a-WLS complex binds to calreticulin (CALR), 
      revealing that CALR functions as a chaperone to facilitate Wnt transfer from 
      PORCN to WLS during Wnt biogenesis. Our structures, functional analyses, and 
      molecular dynamics simulations demonstrate that a phospholipid in the core of 
      Wnt-bound WLS regulates the association and dissociation between Wnt and WLS, 
      suggesting a lipid-mediated Wnt secretion mechanism. Finally, the structure of 
      Wnt7a bound to RECK, a cell-surface Wnt7 co-receptor, reveals how RECK(CC4) 
      engages the N-terminal domain of Wnt7a to activate Wnt7-specific signaling.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Qi, Xiaofeng
AU  - Qi X
AD  - Department of Molecular Genetics, University of Texas Southwestern Medical 
      Center, Dallas, TX 75390, USA. Electronic address: 
      xiaofeng.qi@utsouthwestern.edu.
FAU - Hu, Qinli
AU  - Hu Q
AD  - Department of Molecular Genetics, University of Texas Southwestern Medical 
      Center, Dallas, TX 75390, USA.
FAU - Elghobashi-Meinhardt, Nadia
AU  - Elghobashi-Meinhardt N
AD  - School of Chemistry, University College Dublin, South Belfield, Dublin 4, 
      Ireland.
FAU - Long, Tao
AU  - Long T
AD  - Department of Molecular Genetics, University of Texas Southwestern Medical 
      Center, Dallas, TX 75390, USA.
FAU - Chen, Hongwen
AU  - Chen H
AD  - Department of Molecular Genetics, University of Texas Southwestern Medical 
      Center, Dallas, TX 75390, USA.
FAU - Li, Xiaochun
AU  - Li X
AD  - Department of Molecular Genetics, University of Texas Southwestern Medical 
      Center, Dallas, TX 75390, USA; Department of Biophysics, University of Texas 
      Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: 
      xiaochun.li@utsouthwestern.edu.
LA  - eng
GR  - P01 HL160487/HL/NHLBI NIH HHS/United States
GR  - R01 GM135343/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20231017
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (WNT7A protein, human)
RN  - 0 (Wnt Proteins)
SB  - IM
MH  - Blood-Brain Barrier/metabolism
MH  - Protein Binding
MH  - *Receptors, G-Protein-Coupled/metabolism
MH  - *Wnt Signaling Pathway
MH  - Humans
MH  - *Wnt Proteins/chemistry/metabolism
PMC - PMC10841698
MID - NIHMS1935389
OTO - NOTNLM
OT  - N-glycan
OT  - Porcupine
OT  - RECK
OT  - Wnt
OT  - Wntless
OT  - calreticulin
OT  - cryo-EM
OT  - phospholipid
COIS- Declaration of interests The authors declare no competing interests.
EDAT- 2023/10/19 00:43
MHDA- 2023/11/13 06:43
PMCR- 2024/11/09
CRDT- 2023/10/18 18:44
PHST- 2023/07/23 00:00 [received]
PHST- 2023/09/04 00:00 [revised]
PHST- 2023/09/21 00:00 [accepted]
PHST- 2024/11/09 00:00 [pmc-release]
PHST- 2023/11/13 06:43 [medline]
PHST- 2023/10/19 00:43 [pubmed]
PHST- 2023/10/18 18:44 [entrez]
AID - S0092-8674(23)01075-9 [pii]
AID - 10.1016/j.cell.2023.09.021 [doi]
PST - ppublish
SO  - Cell. 2023 Nov 9;186(23):5028-5040.e14. doi: 10.1016/j.cell.2023.09.021. Epub 
      2023 Oct 17.