MyTH4-FERM myosins in the assembly and maintenance of actin-based protrusions

Weck, Meredith L.; Grega-Larson, Nathan E.; Tyska, Matthew J.

doi:10.1016/j.ceb.2016.10.002

Cited by 33 publications

(38 citation statements)

References 154 publications

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“…Myo10 is a member of a phylogenetically ancient group of myosins characterized by one or more MyTH4-FERM domains (Myosin Tail Homology 4 and band 4.1, Ezrin, Radixin, Merlin). The MyTH4-FERM myosins are strongly associated with protrusions based on actin bundles, such as filopodia, microvilli, and inner ear stereocilia 10 , 11 . Of the four MyTH4-FERM myosins expressed in humans, Myo7a is expressed in several tissues and localizes to inner ear stereocilia 12 , Myo7b is expressed in transporting epithelia and localizes to the tips of microvilli 13 , Myo15a is expressed in the inner ear and localizes to the tips of stereocilia 14 , and Myo10 is expressed in most cells and localizes to the tips of filopodia 3 .…”

Section: Introductionmentioning

confidence: 99%

Myosin-X knockout is semi-lethal and demonstrates that myosin-X functions in neural tube closure, pigmentation, hyaloid vasculature regression, and filopodia formation

Heimsath

Yim

Mustapha

et al. 2017

Sci Rep

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Myosin-X (Myo10) is an unconventional myosin best known for its striking localization to the tips of filopodia. Despite the broad expression of Myo10 in vertebrate tissues, its functions at the organismal level remain largely unknown. We report here the generation of KO-first (Myo10 tm1a/tm1a), floxed (Myo10 tm1c/tm1c), and KO mice (Myo10 tm1d/tm1d). Complete knockout of Myo10 is semi-lethal, with over half of homozygous KO embryos exhibiting exencephaly, a severe defect in neural tube closure. All Myo10 KO mice that survive birth exhibit a white belly spot, all have persistent fetal vasculature in the eye, and ~50% have webbed digits. Myo10 KO mice that survive birth can breed and produce litters of KO embryos, demonstrating that Myo10 is not absolutely essential for mitosis, meiosis, adult survival, or fertility. KO-first mice and an independent spontaneous deletion (Myo10 m1J/m1J) exhibit the same core phenotypes. During retinal angiogenesis, KO mice exhibit a ~50% decrease in endothelial filopodia, demonstrating that Myo10 is required to form normal numbers of filopodia in vivo. The Myo10 mice generated here demonstrate that Myo10 has important functions in mammalian development and provide key tools for defining the functions of Myo10 in vivo.

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Section: Introductionmentioning

confidence: 99%

Myosin-X knockout is semi-lethal and demonstrates that myosin-X functions in neural tube closure, pigmentation, hyaloid vasculature regression, and filopodia formation

Heimsath

Yim

Mustapha

et al. 2017

Sci Rep

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“…In addition to Myo7b, Myo7a, Myo10, and Myo15a also contain one or two MyTH4-FERM tandems in their tail domains (14). A common property of MyTH4-FERM myosins is their involvement in the formation or elongation/stabilization of actin-bundle supported structures, including filopodia, microvilli, and stereocilia (15). This property first appeared in ancient MyTH4-FERM myosins and is conserved over 1 billion y of evolution (14,16,17).…”

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confidence: 99%

Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins

Weck

et al. 2017

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

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Unconventional myosin 7a (Myo7a), myosin 7b (Myo7b), and myosin 15a (Myo15a) all contain MyTH4-FERM domains (myosin tail homology 4-band 4.1, ezrin, radixin, moesin; MF) in their cargo binding tails and are essential for the growth and function of microvilli and stereocilia. Numerous mutations have been identified in the MyTH4-FERM tandems of these myosins in patients suffering visual and hearing impairment. Although a number of MF domain binding partners have been identified, the molecular basis of interactions with the C-terminal MF domain (CMF) of these myosins remains poorly understood. Here we report the high-resolution crystal structure of Myo7b CMF in complex with the extended PDZ3 domain of USH1C (a.k.a., Harmonin), revealing a previously uncharacterized interaction mode both for MyTH4-FERM tandems and for PDZ domains. We predicted, based on the structure of the Myo7b CMF/USH1C PDZ3 complex, and verified that Myo7a CMF also binds to USH1C PDZ3 using a similar mode. The structure of the Myo7b CMF/USH1C PDZ complex provides mechanistic explanations for >20 deafness-causing mutations in Myo7a CMF. Taken together, these findings suggest that binding to PDZ domains, such as those from USH1C, PDZD7, and Whirlin, is a common property of CMFs of Myo7a, Myo7b, and Myo15a.M icrovilli and stereocilia are both actin bundle-based, fingerlike protrusions found on apical surfaces of many epithelial cells (1). Microvilli line the apical surface of epithelial cells forming a densely packed structure known as the brush border in tube-like tissues, such as intestines, kidney, and lung (2-5). The best known function of microvilli is to massively increase membrane surface area of these tissues to promote solute exchange, although these protrusions may also allow cells to communicate with their extracellular surroundings (6). Stereocilia, on the other hand, are composed of several rows of protrusions with graded height forming a staircase-like structure on the apical surface of inner ear hair cells, which collectively function to sense sound waves (7,8). Despite clear morphological and functional differences, microvilli and stereocilia share certain features at the molecular level. For example, the packing and organization of microvilli and stereocilia both rely on homologous cadherin-based tip-link complexes that target to the distal ends of these protrusions (9, 10). Additionally, a set of homologous unconventional myosins-including Myo1, Myo3, Myo6, and Myo7-are shared by and critical for the development, maintenance, and functions of microvilli and stereocilia (1,11,12).This study focuses on Myo7b, an unconventional myosin enriched in the microvilli of transporting epithelial cells (11, 13). Myo7b is characterized by a pair of MyTH4-FERM tandems in its tail cargo-binding domain. In addition to Myo7b, Myo7a, Myo10, and Myo15a also contain one or two MyTH4-FERM tandems in their tail domains (14). A common property of MyTH4-FERM myosins is their involvement in the formation or elongation/stabilization of actin-bundle support...

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“…It is located in the second FERM domain of the MYO15A protein. Previous reports suggested that the MyTH4-FERM domain is required for its localization to stereocilia tips and enriching the adhesion molecules, actin-regulatory proteins [ 23 ]. Mutations in this domain could also r result in losing the normal function of the MYO15A protein.…”

Section: Discussionmentioning

confidence: 99%

A novel nonsense mutation in MYO15A is associated with non-syndromic hearing loss: a case report

Shen

Gao

et al. 2018

BMC Med Genet

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BackgroundHearing loss is genetically heterogeneous and is one of the most common human defects. Here we screened the underlying mutations that caused autosomal recessive non-syndromic hearing loss in a Chinese family.Case presentationThe proband with profound hearing loss had received audiometric assessments. We performed target region capture and next generation sequencing of 127 known deafness-related genes because the individual tested negative for hotspot variants in the GJB2, GJB3, SLC26A4, and MTRNR1 genes. We identified a novel c.6892C > T (p.R2298*) nonsense mutation and a c.10251_10253delCTT (p.F3420del) deletion in MYO15A. Sanger sequencing confirmed that both mutations were co-segregated with hearing loss in this family and were absent in 200 ethnically matched controls. Bioinformatics analysis and protein modeling indicated the deleterious effects of both mutations. The p.R2298* mutation leads to a truncated protein and a loss of the functional domains.ConclusionsOur results demonstrated that the hearing loss in this case was caused by novel, compound heterozygous mutations in MYO15A. The p.R2298* mutation in MYO15A was reported for the first time, which has implications for genetic counseling and provides insight into the functional roles of MYO15A mutations.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0657-y) contains supplementary material, which is available to authorized users.

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MyTH4-FERM myosins in the assembly and maintenance of actin-based protrusions

Cited by 33 publications

References 154 publications

Myosin-X knockout is semi-lethal and demonstrates that myosin-X functions in neural tube closure, pigmentation, hyaloid vasculature regression, and filopodia formation

Myosin-X knockout is semi-lethal and demonstrates that myosin-X functions in neural tube closure, pigmentation, hyaloid vasculature regression, and filopodia formation

Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins

A novel nonsense mutation in MYO15A is associated with non-syndromic hearing loss: a case report

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