8BRG

Crystal structure of She4

Summary for 8BRG

• Entry DOI: 10.2210/pdb8brg/pdb
• Related: 8BRH
• Descriptor: KLLA0E16699p (2 entities in total)
• Functional Keywords: unc-45, ucs, myosin, chaperone
• Biological source: Kluyveromyces lactis
• Total number of polymer chains: 1
• Total formula weight: 75856.88

Authors

Gudino, R.,Arnese, R.,Meinhart, A.,Clausen, T. (deposition date: 2022-11-23, release date: 2024-06-05, Last modification date: 2024-08-14)

Primary citation

Vogel, A.,Arnese, R.,Gudino Carrillo, R.M.,Sehr, D.,Deszcz, L.,Bylicki, A.,Meinhart, A.,Clausen, T.
UNC-45 assisted myosin folding depends on a conserved FX 3 HY motif implicated in Freeman Sheldon Syndrome.
Nat Commun, 15:6272-6272, 2024

PubMed 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 FXHY 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 FXHY 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.

PubMed: 39054317
DOI: 10.1038/s41467-024-50442-6

Experimental method

X-RAY DIFFRACTION (2.4 Å)