Myosin VII, USH1C, and ANKS4B or USH1G Together Form Condensed Molecular Assembly via Liquid-Liquid Phase Separation

He, Yunyun; Li, J.; Zhang, Mingjie

doi:10.1016/j.celrep.2019.09.027

Cited by 33 publications

(38 citation statements)

References 64 publications

(126 reference statements)

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“…IDPs are known to drive the formation of both organelles by liquid-liquid phase separation (LLPS) (9,70,71). Recently, it has been suggested that SANS generates protein condensates via LLPS as part of the tip-link complex in stereocilia of inner ear hair cells (33). SANS may change the material properties in the tip-link complex and in the absence of SANS, the tip-link complex of hair cells loose its integrity (32).…”

Section: Sans Interacts Through An Intrinsically Disordered Region Wimentioning

confidence: 99%

“…Pathogenic variants in USH1G cause human USH1, a ciliopathy characterized by sensory neuronal degenerations leading to profound hearing loss, vestibular dysfunction and vision loss in the form of Retinitis pigmentosa (RP) (24). While in the inner ear the essential roles of SANS in hair cell differentiation and the mechano-electrical signal transduction complex can well explain the pathophysiology in USH1G (31)(32)(33), the ophthalmic pathogenesis in the retina is still puzzling (78). Links between the USH1G protein SANSor any other USH1 proteinsand the splicing machinery of cells has not been reported yet.…”

Section: Sans/ush1g Mutations Lead To Ush Due To Splicing Defects In mentioning

confidence: 99%

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SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes

Yıldırım

Mozaffari‐Jovin

Wallisch

et al. 2020

Preprint

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Splicing is catalyzed by the spliceosome, a compositionally dynamic complex assembled stepwise on pre-mRNA. We reveal the link between splicing machinery components with the intrinsically disordered ciliopathy protein SANS. Pathogenic mutations in SANS/USH1G lead to Usher syndrome – the most common cause of deaf-blindness. SANS functions has been associated with cytoplasmic processes so far. Here, we show SANS localization in Cajal bodies and nuclear speckles. There SANS interacts with components of spliceosomal complexes and the large splicing cofactor SON and PRPFs of the tri-snRNP complex. SANS is required for the release of tri-snRNPs from Cajal bodies and their recruitment to nuclear speckles. SANS depletion alters spliceosome assembly kinetics, leading to stalled complex A formation, which can be chased to spliced products by the addition of tri-snRNPs. SANS deficiency and USH1G mutations affects splicing of genes related to cell proliferation and USH. We provide the first evidence that splicing deregulation may participate at the pathophysiology of Usher syndrome.

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Section: Sans Interacts Through An Intrinsically Disordered Region Wimentioning

confidence: 99%

Section: Sans/ush1g Mutations Lead To Ush Due To Splicing Defects In mentioning

confidence: 99%

SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes

Yıldırım

Mozaffari‐Jovin

Wallisch

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The extracellular domains of CDH23 and protocadherin 15 (PCDH15) bind to one another to form the stereociliary tip link required to open stretch-activated channels located at the tip of the shorter stereocilium. For simplicity, only one copy of each protein is shown in these diagrams even though the myosin-7's and the cadherin superfamily proteins are likely to function as homodimers or higher-order oligomers, and the complexes themselves may form protein condensates (11). For a more detailed summary of protein interactions, see Ref.…”

Section: Conflict Of Interest-mentioning

confidence: 99%

A new light chain for myosin-7

Kapustina

Cheney

2020

Journal of Biological Chemistry

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Recent research has revealed that an adhesion complex based on cadherins and the motor protein myosin-7b (MYO7B) links the tips of intestinal microvilli. Choi et al. now report that a largely uncharacterized protein known as calmodulin-like protein 4 (CALML4) is a component of this adhesion complex and functions as a light chain for myosin-7b. Because the intermicrovillar adhesion complex is homologous to the myosin-7a (MYO7A)-based Usher syndrome complex and Choi et al. also report that CALML4 can bind to myosin-7a, this work also has important implications for research on myosin-7a and hereditary deaf-blindness.

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“…Whereas most of the binary interactions in the IMAC exhibit affinities in the range of ~1-5 µM (8,12,13), the ANKS4B Cterminus binds to the USH1C N-terminal PDZ domain with a much higher affinity in the nM range (12,13). The extensive network of multivalent interactions among IMAC components may also lead to liquid-liquid phase separation upon complex formation (32).…”

Section: Introductionmentioning

confidence: 99%

A heterologous in-cell assay for investigating intermicrovillar adhesion complex interactions reveals a novel protrusion length-matching mechanism

Weck

Crawley

Tyska

2020

Journal of Biological Chemistry

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Solute transporting epithelial cells build arrays of microvilli on their apical surface to increase membrane scaffolding capacity and enhance function potential. In epithelial tissues such as the kidney and gut, microvilli are length-matched and assembled into tightly packed ‘brush borders’, which are organized by ~50 nm thread-like links that form between the distal tips of adjacent protrusions. Composed of protocadherins CDHR2 and CDHR5, adhesion links are stabilized at the tips by a cytoplasmic tripartite module containing the scaffolds USH1C and ANKS4B, and the actin-based motor, MYO7B. As several questions about the formation and function of this ‘intermicrovillar adhesion complex’ remain open, we devised a system that allows one to study individual binary interactions between specific complex components and MYO7B. Our approach employs a chimeric myosin consisting of the MYO10 motor domain fused to the MYO7B cargo-binding tail domain. When expressed in HeLa cells, which do not normally produce adhesion complex proteins, this chimera trafficked to the tips of filopodia and was also able to transport individual complex components to these sites. Unexpectedly, the MYO10-MYO7B chimera was able to deliver CDHR2 and CDHR5 to distal tips in the absence USH1C or ANKS4B. Cells engineered to localize high levels of CDHR2 at filopodial tips acquired inter-filopodial adhesion and exhibited a striking dynamic length matching activity that aligned distal tips over time. These findings deepen our understanding of mechanisms that promote the distal tip accumulation of intermicrovillar adhesion complex components and also offer insight on how epithelial cells minimize microvillar length variability.

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Myosin VII, USH1C, and ANKS4B or USH1G Together Form Condensed Molecular Assembly via Liquid-Liquid Phase Separation

Cited by 33 publications

References 64 publications

SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes

SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes

A new light chain for myosin-7

A heterologous in-cell assay for investigating intermicrovillar adhesion complex interactions reveals a novel protrusion length-matching mechanism

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