Intermolecular Autophosphorylation Regulates Myosin IIIa Activity and Localization in Parallel Actin Bundles

Quintero, Omar A.; Moore, Judy E.; Unrath, William C.; Manor, Uri; Salles, Felipe T.; Grati, M’hamed; Kachar, Bechara; Yengo, Christopher M.

doi:10.1074/jbc.m110.144360

Cited by 40 publications

(89 citation statements)

References 46 publications

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“…The T184E and T184A mutations were also introduced in the full-length GFP-tagged version of MYO3A for expression in COS7 cells (3). We generated a construct containing only the MYO3A kinase domain (MYO3 kinase, residues 1-339).…”

Section: Methodsmentioning

confidence: 99%

“…Protein Expression and Purification-The MYO3A kinase and MYO3A 2IQ constructs were expressed with the baculovirus/SF9 cell system and purified as described (3,23,24). Protein purity was assessed by Coomassie-stained SDS-polyacrylamide gels, and protein concentration was determined by the Bradford assay using BSA as a standard or by absorbance using the predicted extinction coefficients (3,23,24).…”

Section: Methodsmentioning

confidence: 99%

“…Reagents-ATP and ADP were prepared from powder (22 (3,23,24) was modified with site-directed mutagenesis to introduce the phosphorylation site mutations (T178A and T178D; T184A and T184E) and a mutation to abolish motor activity (E722A). The T184E and T184A mutations were also introduced in the full-length GFP-tagged version of MYO3A for expression in COS7 cells (3).…”

Section: Methodsmentioning

confidence: 99%

“…However, the regulatory role and potential biological function of the phosphorylation sites were not investigated. Based on studies of MYO3A, we have proposed a model of class III myosin regulation in the actin bundle-based structures (3). In this model, MYO3A translocates to the tips of actin bundlebased structures with an active dephosphorylated motor domain.…”

mentioning

confidence: 99%

“…The kinase domain of vertebrate class III myosins is a member of the sterile-20 (STE20) 3 family of kinases (16). Many members of the STE20 family of kinases as well as other kinase families are regulated by autophosphorylation (17).…”

mentioning

confidence: 99%

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Myosin 3A Kinase Activity Is Regulated by Phosphorylation of the Kinase Domain Activation Loop

Quintero

Unrath

Stevens

et al. 2013

Journal of Biological Chemistry

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Background: Class III myosins contain both a motor and kinase domain. Results: Phosphorylation of the kinase activation loop enhances MYO3A kinase activity, augmenting autophosphorylationinduced attenuation of motor and cellular activity. Conclusion: MYO3A kinase activity mediates localization and function within actin protrusions. Significance: Characterizing MYO3A kinase regulation enhances our understanding of the role of MYO3A in the maintenance of actin protrusions found in sensory epithelia.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Myosin 3A Kinase Activity Is Regulated by Phosphorylation of the Kinase Domain Activation Loop

Quintero

Unrath

Stevens

et al. 2013

Journal of Biological Chemistry

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MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform

et al. 2016

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Hereditary hearing loss is characterized by both allelic and locus genetic heterogeneity. Both recessive and dominant forms of hearing loss may be caused by different mutations in the same deafness gene. In a family with post-lingual progressive non-syndromic deafness, whole exome sequencing of genomic DNA from five hearing-impaired relatives revealed a single variant, p.Gly488Glu (rs145970949:G>A) in MYO3A, co-segregating with hearing loss as an autosomal dominant trait. This amino acid change, predicted to be pathogenic, alters a highly conserved residue in the motor domain of MYO3A. The mutation severely alters the ATPase activity and motility of the protein in vitro, and the mutant protein fails to accumulate in the filopodia tips in COS7 cells. However, the mutant MYO3A was able to reach the tips of organotypic inner ear culture hair cell stereocilia, raising the possibility of a local effect on positioning of the mechano-electrical transduction (MET) complex at the stereocilia tips. To address this hypothesis, we investigated the interaction of MYO3A with the cytosolic tail of the integral tip-link protein protocadherin 15 (PCDH15), a core component of MET complex. Interestingly, we uncovered a novel interaction between MYO3A and PCDH15 shedding new light on the function of myosin IIIA at stereocilia tips.

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A novel missense variant in MYO3A is associated with autosomal dominant high‐frequency hearing loss in a German family

Doll¹,

Hofrichter²,

Bahena³

et al. 2020

Molec Gen & Gen Med

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Background MYO3A , encoding the myosin IIIA protein, is associated with autosomal recessive and autosomal dominant nonsyndromic hearing loss. To date, only two missense variants located in the motor‐head domain of MYO3A have been described in autosomal dominant families with progressive, mild‐to‐profound sensorineural hearing loss. These variants alter the ATPase activity of myosin IIIA. Methods Exome sequencing of a proband from a three‐generation German family with prelingual, moderate‐to‐profound, high‐frequency hearing loss was performed. Segregation analysis confirmed a dominant inheritance pattern. Regression analysis of mean hearing level thresholds per individual and ear was performed at high‐, mid‐, and low‐frequencies. Results A novel heterozygous missense variant c.716T>C, p.(Leu239Pro) in the kinase domain of MYO3A was identified that is predicted in silico as disease causing. High‐frequency, progressive hearing loss was identified. Conclusion Correlation analysis of pure‐tone hearing thresholds revealed progressive hearing loss, especially in the high‐frequencies. In the present study, we report the first dominant likely pathogenic variant in MYO3A in a European family and further support MYO3A as an autosomal dominant hearing loss gene.

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Intermolecular Autophosphorylation Regulates Myosin IIIa Activity and Localization in Parallel Actin Bundles

Cited by 40 publications

References 46 publications

Myosin 3A Kinase Activity Is Regulated by Phosphorylation of the Kinase Domain Activation Loop

Myosin 3A Kinase Activity Is Regulated by Phosphorylation of the Kinase Domain Activation Loop

MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform

A novel missense variant in MYO3A is associated with autosomal dominant high‐frequency hearing loss in a German family

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