PXD040428-1

PXD040428 is an original dataset announced via ProteomeXchange.

Title	UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome
Description	Myosin motors are critical for diverse motility functions ranging from cytokinesis and endocytosis to muscle contraction. The UNC-45 chaperone controls myosin function mediating the folding, assembly, and degradation of the muscle protein. Here, we analyze the molecular mechanism of UNC-45 as a hub in myosin quality control. We show that UNC-45 forms discrete complexes with folded and unfolded myosin, forwarding them to downstream chaperones and E3 ligases. Structural analysis of a minimal chaperone:substrate complex reveals that UNC-45 binds to a conserved FX3HY motif in the myosin motor domain. Disrupting the observed interface by mutagenesis prevents myosin maturation leading to protein aggregation in vivo. We also show that a mutation in the FX3HY motif linked to the Freeman Sheldon Syndrome impairs UNC-45 assisted folding, reducing the level of functional myosin. These findings demonstrate that a faulty myosin quality control is a critical yet unexplored cause of human myopathies.
HostingRepository	PRIDE
AnnounceDate	2024-07-25
AnnouncementXML	Submission_2024-07-25_09:51:58.004.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Richard Imre
SpeciesList	scientific name: Caenorhabditis elegans; NCBI TaxID: 6239;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF; Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-27 05:19:31	ID requested
⏵ 1	2024-07-25 09:51:58	announced
2	2024-10-22 06:51:24	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: UFD-2, myopathy, MHC-B, Myo4,protein quality control, crosslinking mass spectrometry, ubiquitin proteasome system, UNC-45, molecular chaperones, myosin proteostasis

Tim Clausen
contact affiliation	Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
contact email	tim.clausen@imp.ac.at
lab head
Richard Imre
contact affiliation	IMBA Vienna
contact email	richard.imre@imba.oeaw.ac.at
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040428
     1. Label: PRIDE project
     2. Name: UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome