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UNC-45 assisted myosin folding depends on a conserved FX₃HY motif implicated in Freeman Sheldon Syndrome.

ABSTRACT: 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.

SUBMITTER: Vogel A

PROVIDER: S-EPMC11272940 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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UNC-45 assisted myosin folding depends on a conserved FX<sub>3</sub>HY motif implicated in Freeman Sheldon Syndrome.

Vogel Antonia A Arnese Renato R Gudino Carrillo Ricardo M RM Sehr Daria D Deszcz Luiza L Bylicki Andrzej A Meinhart Anton A Clausen Tim T

Nature communications 20240725 1

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 chap ...[more]

PMID: 39054317

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Project description:IntroductionFreeman-Sheldon syndrome (FSS), also known as the distal arthrogryposis (DA) type 2A, is a rare congenital anomaly. We report a unique case of the DA type 2A with mixed clinical features and the unusual presentation of bilateral congenital dislocation of the knee but had unassisted stiff knee gait.Case reportA 5-year-old female child presented to the clinic with the complaint of inability to bend both knees since birth. She had an unassisted bipedal gait, but could not squat, cross-leg sit, run, and climb stairs without assistance. Her youngest brother had a similar presentation but succumbed to death at the age of 5 months due to respiratory distress. Clinical features were in the favor of FSS. Her serum creatinine kinase level was normal and the electromyography of bilateral tibialis anterior and abductor pollicis brevis was not suggestive of the myotonia. Radiograph of the skull showed cooper beaten skull appearance whereas bilateral pelvis with the hip showed following changes in the right hip; decrease femoral epiphysis height, horizontal proximal femoral physis, and the coxa brevia. She was initially managed conservatively by weekly stretching, manipulation, and casting. As a result, she could flex her knee up to 20°. Although the quadricepsplasty might be helpful for the persistent extension deformity, there was marked quadriceps weakness which could make it harder for the child to stand and walk. In addition, the abnormal muscle physiology in FSS may result in unfavorable outcomes after the surgery. Moreover, a consideration of the surgical aspect is not free of risks which include difficult endotracheal intubation, vein access, and malignant hyperthermia.ConclusionFSS is a rare congenital anomaly that should be differentiated from another syndrome of the close resemblance, Sheldon Hall syndrome and Schwartz Jampel syndrome which are other rare autosomal recessive disorders characterized by myotonia and the chondrodysplasia. Conservative management has still a role in bilateral knee involvement especially if the patient is an independent walker.

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UNC-45 assisted myosin folding depends on a conserved FX₃HY motif implicated in Freeman Sheldon Syndrome.

Publications

UNC-45 assisted myosin folding depends on a conserved FX<sub>3</sub>HY motif implicated in Freeman Sheldon Syndrome.

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Dataset Information

UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome.

Publications

UNC-45 assisted myosin folding depends on a conserved FX<sub>3</sub>HY motif implicated in Freeman Sheldon Syndrome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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UNC-45 assisted myosin folding depends on a conserved FX₃HY motif implicated in Freeman Sheldon Syndrome.