PMID- 37356721
OWN - NLM
STAT- MEDLINE
DCOM- 20230901
LR  - 20230906
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 299
IP  - 8
DP  - 2023 Aug
TI  - The collagen ColQ binds to LRP4 and regulates the activation of the 
      Muscle-Specific Kinase-LRP4 receptor complex by agrin at the neuromuscular 
      junction.
PG  - 104962
LID - S0021-9258(23)01990-7 [pii]
LID - 10.1016/j.jbc.2023.104962 [doi]
LID - 104962
AB  - Collagen Q (ColQ) is a nonfibrillar collagen that plays a crucial role at the 
      vertebrate neuromuscular junction (NMJ) by anchoring acetylcholinesterase to the 
      synapse. ColQ also functions in signaling, as it regulates acetylcholine receptor 
      clustering and synaptic gene expression, in a manner dependent on muscle-specific 
      kinase (MuSK), a key protein in NMJ formation and maintenance. MuSK forms a 
      complex with low-density lipoprotein receptor-related protein 4 (LRP4), its 
      coreceptor for the proteoglycan agrin at the NMJ. Previous studies suggested that 
      ColQ also interacts with MuSK. However, the molecular mechanisms underlying ColQ 
      functions and ColQ-MuSK interaction have not been fully elucidated. Here, we 
      investigated whether ColQ binds directly to MuSK and/or LRP4 and whether it 
      modulates agrin-mediated MuSK-LRP4 activation. Using coimmunoprecipitation, 
      pull-down, plate-binding assays, and surface plasmon resonance, we show that ColQ 
      binds directly to LRP4 but not to MuSK and that ColQ interacts indirectly with 
      MuSK through LRP4. In addition, we show that the LRP4 N-terminal region, which 
      contains the agrin-binding sites, is also crucial for ColQ binding to LRP4. 
      Moreover, ColQ-LRP4 interaction was reduced in the presence of agrin, suggesting 
      that agrin and ColQ compete for binding to LRP4. Strikingly, we reveal ColQ has 
      two opposing effects on agrin-induced MuSK-LRP4 signaling: it constitutively 
      reduces MuSK phosphorylation levels in agrin-stimulated myotubes but 
      concomitantly increases MuSK accumulation at the muscle cell surface. Our results 
      identify LRP4 as a major receptor of ColQ and provide new insights into 
      mechanisms of ColQ signaling and acetylcholinesterase anchoring at the NMJ.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Uyen Dao, Thi Minh
AU  - Uyen Dao TM
AD  - Universite Paris Cite, CNRS, Saints-Peres Paris Institute for the Neurosciences, 
      Paris, France.
FAU - Barbeau, Susie
AU  - Barbeau S
AD  - Universite Paris Cite, CNRS, Saints-Peres Paris Institute for the Neurosciences, 
      Paris, France.
FAU - Messeant, Julien
AU  - Messeant J
AD  - Universite Paris Cite, CNRS, Saints-Peres Paris Institute for the Neurosciences, 
      Paris, France.
FAU - Della-Gaspera, Bruno
AU  - Della-Gaspera B
AD  - Universite Paris Cite, INSERM UMR-S 1124, Paris, France.
FAU - Bouceba, Tahar
AU  - Bouceba T
AD  - Sorbonne Universite, CNRS, IBPS, Protein Engineering Platform, Paris, France.
FAU - Semprez, Fannie
AU  - Semprez F
AD  - Universite Paris Cite, CNRS, Saints-Peres Paris Institute for the Neurosciences, 
      Paris, France.
FAU - Legay, Claire
AU  - Legay C
AD  - Universite Paris Cite, CNRS, Saints-Peres Paris Institute for the Neurosciences, 
      Paris, France.
FAU - Dobbertin, Alexandre
AU  - Dobbertin A
AD  - Universite Paris Cite, CNRS, Saints-Peres Paris Institute for the Neurosciences, 
      Paris, France. Electronic address: alexandre.dobbertin@u-paris.fr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230623
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - EC 3.1.1.7 (Acetylcholinesterase)
RN  - 0 (Agrin)
RN  - 9007-34-5 (Collagen)
RN  - EC 3.1.1.7 (COLQ protein, human)
RN  - 0 (LDL-Receptor Related Proteins)
RN  - 0 (LRP4 protein, human)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (MUSK protein, human)
SB  - IM
MH  - Humans
MH  - *Acetylcholinesterase/metabolism
MH  - *Agrin/genetics/metabolism
MH  - *Collagen/metabolism
MH  - LDL-Receptor Related Proteins/genetics/metabolism
MH  - Muscle Fibers, Skeletal/metabolism
MH  - *Neuromuscular Junction/metabolism
MH  - Receptor Protein-Tyrosine Kinases/metabolism
PMC - PMC10382678
OTO - NOTNLM
OT  - AChE
OT  - ColQ
OT  - LRP4
OT  - MuSK
OT  - agrin
OT  - myasthenic syndromes
OT  - neuromuscular junction
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2023/06/26 00:41
MHDA- 2023/08/31 06:42
PMCR- 2023/06/23
CRDT- 2023/06/25 19:17
PHST- 2022/04/20 00:00 [received]
PHST- 2023/06/09 00:00 [revised]
PHST- 2023/06/13 00:00 [accepted]
PHST- 2023/08/31 06:42 [medline]
PHST- 2023/06/26 00:41 [pubmed]
PHST- 2023/06/25 19:17 [entrez]
PHST- 2023/06/23 00:00 [pmc-release]
AID - S0021-9258(23)01990-7 [pii]
AID - 104962 [pii]
AID - 10.1016/j.jbc.2023.104962 [doi]
PST - ppublish
SO  - J Biol Chem. 2023 Aug;299(8):104962. doi: 10.1016/j.jbc.2023.104962. Epub 2023 
      Jun 23.