Myosin chaperones

Hellerschmied, Doris; Clausen, Tim

doi:10.1016/j.sbi.2013.11.002

Cited by 33 publications

(31 citation statements)

References 48 publications

(32 reference statements)

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“…On reaching the site of assembly, molecules could be triggered to unfold and incorporate into nascent filaments, e.g., by interaction with titin or myosin tails on the filament surface. Myosin chaperones may also play a role in this process (97,98). This model would be analogous to the synthesis of collagen inside fibroblasts, where intracellular assembly of procollagen molecules into fibrils is prevented by the presence of bulky peptides at the molecular ends.…”

Section: Discussionmentioning

confidence: 99%

Interacting-heads motif has been conserved as a mechanism of myosin II inhibition since before the origin of animals

Lee

Sulbarán

Yang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

109

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Electron microscope studies have shown that the switched-off state of myosin II in muscle involves intramolecular interaction between the two heads of myosin and between one head and the tail. The interaction, seen in both myosin filaments and isolated molecules, inhibits activity by blocking actin-binding and ATPase sites on myosin. This interacting-heads motif is highly conserved, occurring in invertebrates and vertebrates, in striated, smooth, and nonmuscle myosin IIs, and in myosins regulated by both Ca binding and regulatory light-chain phosphorylation. Our goal was to determine how early this motif arose by studying the structure of inhibited myosin II molecules from primitive animals and from earlier, unicellular species that predate animals. Myosin II from (sea anemones, jellyfish), the most primitive animals with muscles, and (sponges), the most primitive of all animals (lacking muscle tissue) showed the same interacting-heads structure as myosins from higher animals, confirming the early origin of the motif. The social amoeba showed a similar, but modified, version of the motif, while the amoeba and fission yeast () showed no head-head interaction, consistent with the different sequences and regulatory mechanisms of these myosins compared with animal myosin IIs. Our results suggest that head-head/head-tail interactions have been conserved, with slight modifications, as a mechanism for regulating myosin II activity from the emergence of the first animals and before. The early origins of these interactions highlight their importance in generating the inhibited (relaxed) state of myosin in muscle and nonmuscle cells.

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Section: Discussionmentioning

confidence: 99%

Interacting-heads motif has been conserved as a mechanism of myosin II inhibition since before the origin of animals

Lee

Sulbarán

Yang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

109

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“…Several other classes of unconventional myosin are reported to interact with UCS domain-containing proteins (25,26). We are now investigating whether individually tailored combinations of UNC-45 and HSP90 isoforms might optimize expression of other myosin heavy chains in Sf9 cells.…”

Section: Discussionmentioning

confidence: 99%

Chaperone-enhanced purification of unconventional myosin 15, a molecular motor specialized for stereocilia protein trafficking

Bird

Takagi

Billington

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Unconventional myosin 15 is a molecular motor expressed in inner ear hair cells that transports protein cargos within developing mechanosensory stereocilia. Mutations of myosin 15 cause profound hearing loss in humans and mice; however, the properties of this motor and its regulation within the stereocilia organelle are unknown. To address these questions, we expressed a subfragment 1-like (S1) truncation of mouse myosin 15, comprising the predicted motor domain plus three light-chain binding sites. Following unsuccessful attempts to express functional myosin 15-S1 using the Spodoptera frugiperda (Sf9)-baculovirus system, we discovered that coexpression of the muscle-myosin-specific chaperone UNC45B, in addition to the chaperone heat-shock protein 90 (HSP90) significantly increased the yield of functional protein. Surprisingly, myosin 15-S1 did not bind calmodulin with high affinity. Instead, the IQ domains bound essential and regulatory light chains that are normally associated with class II myosins. We show that myosin 15-S1 is a barbed-end-directed motor that moves actin filaments in a gliding assay (∼430 nm·s −1 at 30°C), using a power stroke of 7.9 nm. The maximum ATPase rate (k cat ∼6 s ) was similar to the actin-detachment rate (k det = 6.2 s −1 ) determined in single molecule optical trapping experiments, indicating that myosin 15-S1 was rate limited by transit through strongly actin-bound states, similar to other processive myosin motors. Our data further indicate that in addition to folding muscle myosin, UNC45B facilitates maturation of an unconventional myosin. We speculate that chaperone coexpression may be a simple method to optimize the purification of other myosin motors from Sf9 insect cells.U nconventional myosin 15 is expressed by inner ear hair cells and accumulates at the tips of mechanosensory stereocilia (1, 2), actin-based organelles that are stimulated by sound and accelerations. A missense substitution in the myosin 15 motor domain results in abnormally short stereocilia in the Myo15 sh2/sh2

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“…Instead, molecular chaperones work in a precise network to allow a nascent myosin polypeptide to be protected from aggregation and folded into its native and functional conformation. The UNC-45B chaperone is associated with the proper folding and function of the sarcomeric myosin [1][2][3][4].UNC-45B is built of three domains: the C-terminal UCS domain, the central domain, and the N-terminal TPR domain [2]. The conserved UCS domain is alone capable to prevent aggregation of the chaperone client protein, myosin, and it is responsible for the chaperonelike properties of UNC-45B [5].…”

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confidence: 99%

mentioning

confidence: 99%

The central domain of UNC‐45 chaperone inhibits the myosin power stroke

et al. 2017

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The multidomain UNC‐45B chaperone is crucial for the proper folding and function of sarcomeric myosin. We recently found that UNC‐45B inhibits the translocation of actin by myosin. The main functions of the UCS and TPR domains are known but the role of the central domain remains obscure. Here, we show—using in vitro myosin motility and ATPase assays—that the central domain alone acts as an inhibitor of the myosin power stroke through a mechanism that allows ATP turnover. Hence, UNC‐45B is a unique chaperone in which the TPR domain recruits Hsp90; the UCS domain possesses chaperone‐like activities; and the central domain interacts with myosin and inhibits the actin translocation function of myosin. We hypothesize that the inhibitory function plays a critical role during the assembly of myofibrils under stress and during the sarcomere development process.

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Myosin chaperones

Abstract: Graphical abstract

Cited by 33 publications

References 48 publications

Interacting-heads motif has been conserved as a mechanism of myosin II inhibition since before the origin of animals

Interacting-heads motif has been conserved as a mechanism of myosin II inhibition since before the origin of animals

Chaperone-enhanced purification of unconventional myosin 15, a molecular motor specialized for stereocilia protein trafficking

The central domain of UNC‐45 chaperone inhibits the myosin power stroke

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