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Mingjie Zhang - One of the best experts on this subject based on the ideXlab platform.
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structure of myo7b ush1c complex suggests a general pdz domain binding mode by myth4 ferm myosins
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Jianchao Li, Yunyun He, Meredith L Weck, Qing Lu, Matthew J Tyska, Mingjie ZhangAbstract: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.
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structure of myo7b ush1c complex suggests a general pdz domain binding mode by myth4 ferm myosins
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Meredith L Weck, Matthew J Tyska, Mingjie ZhangAbstract: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.
Matthew J Tyska - One of the best experts on this subject based on the ideXlab platform.
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structure of myo7b ush1c complex suggests a general pdz domain binding mode by myth4 ferm myosins
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Jianchao Li, Yunyun He, Meredith L Weck, Qing Lu, Matthew J Tyska, Mingjie ZhangAbstract: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.
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structure of myo7b ush1c complex suggests a general pdz domain binding mode by myth4 ferm myosins
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Meredith L Weck, Matthew J Tyska, Mingjie ZhangAbstract: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.
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impact of the motor and tail domains of class iii myosins on regulating the formation and elongation of actin protrusions
Journal of Biological Chemistry, 2016Co-Authors: Manmeet H Raval, Bechara Kachar, Omar A Quintero, Meredith L Weck, Matthew J Tyska, William C Unrath, James W Gallagher, Runjia Cui, Christopher M YengoAbstract:Abstract Class III myosins (MYO3A and MYO3B) are proposed to function as transporters as well as length and ultrastructure regulators within stable actin-based protrusions such as stereocilia and calycal processes. MYO3A differs from MYO3B in that it contains an extended tail domain with an additional actin-binding motif. We examined how the properties of the motor and tail domains of human class III myosins impact their ability to enhance the formation and elongation of actin protrusions. Direct examination of the motor and enzymatic properties of human MYO3A and MYO3B revealed that MYO3A is a 2-fold faster motor with enhanced ATPase activity and actin affinity. A chimera in which the MYO3A tail was fused to the MYO3B motor demonstrated that motor activity correlates with formation and elongation of actin protrusions. We demonstrate that removal of individual exons (30–34) in the MYO3A tail does not prevent filopodia tip localization but abolishes the ability to enhance actin protrusion formation and elongation in COS7 cells. Interestingly, our results demonstrate that MYO3A slows filopodia dynamics and enhances filopodia lifetime in COS7 cells. We also demonstrate that MYO3A is more efficient than MYO3B at increasing formation and elongation of stable microvilli on the surface of cultured epithelial cells. We propose that the unique features of MYO3A, enhanced motor activity, and an extended tail with tail actin-binding motif, allow it to play an important role in stable actin protrusion length and ultrastructure maintenance.
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myosin 1a targets to microvilli using multiple membrane binding motifs in the tail homology 1 th1 domain
Journal of Biological Chemistry, 2012Co-Authors: Jessica N Mazerik, Matthew J TyskaAbstract:One of the most abundant components of the enterocyte brush border is the actin-based monomeric motor, myosin-1a (Myo1a). Within brush border microvilli, Myo1a carries out a number of critical functions at the interface between membrane and actin cytoskeleton. Proper physiological function of Myo1a depends on its ability to bind to microvillar membrane, an interaction mediated by a C-terminal tail homology 1 (TH1) domain. However, little is known about the mechanistic details of the Myo1a-TH1/membrane interaction. Structure-function analysis of Myo1a-TH1 targeting in epithelial cells revealed that an N-terminal motif conserved among class I myosins and a C-terminal motif unique to Myo1a-TH1 are both required for steady state microvillar enrichment. Purified Myo1a bound to liposomes composed of phosphatidylserine and phosphoinositol 4,5-bisphosphate, with moderate affinity in a charge-dependent manner. Additionally, peptides of the N- and C-terminal regions required for targeting were able to compete with Myo1a for binding to highly charged liposomes in vitro. Single molecule total internal reflection fluorescence microscopy showed that these motifs are also necessary for slowing the membrane detachment rate in cells. Finally, Myo1a-TH1 co-localized with both lactadherin-C2 (a phosphatidylserine-binding protein) and PLCδ1-PH (a phosphoinositol 4,5-bisphosphate-binding protein) in microvilli, but only lactaderin-C2 expression reduced brush border targeting of Myo1a-TH1. Together, our results suggest that Myo1a targeting to microvilli is driven by membrane binding potential that is distributed throughout TH1 rather than localized to a single motif. These data highlight the diversity of mechanisms that enable different class I myosins to target membranes in distinct biological contexts.
Fouzia T Javid - One of the best experts on this subject based on the ideXlab platform.
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mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness dfnb2 allele with residual function
Human Mutation, 2008Co-Authors: Sabiha Nazli, Rehan S. Shaikh, Ahmed U Zafar, Farooq Sabar, Fareeha Zulfiqar, Shaheen N Khan, Zubair M Ahmed, Yi Yang, Fouzia T JavidAbstract:Department ofBiology, University of Maryland, College Park, MarylandCommunicated by Dvorah AbeliovichRecessive mutations of MYO7A, encoding unconventional myosin VIIA, can cause either a deaf-blindnesssyndrome (type 1 Usher syndrome; USH1B) or nonsyndromic deafness (DFNB2). In our study, deafnesssegregating as a recessive trait in 24 consanguineous families showed linkage to markers for the DFNB2/USH1B locus on chromosome 11q13.5. A total of 23 of these families segregate USH1 due to 17 homozygousmutant MYO7A alleles, of which 14 are novel. One family segregated nonsyndromic hearing loss DFNB2 due toa novel three-nucleotide deletion in an exon of MYO7A (p.E1716del) encoding a region of the tail domain. Wehypothesized that DFNB2 alleles of MYO7A have residual myosin VIIA. To address this question weinvestigated the effects of several mutant alleles by making green fluorescent protein (GFP) tagged cDNAexpression constructs containing engineered mutations of mouse MYO7A at codons equivalent to pathogenicUSH1B and DFNB2 alleles of human MYO7A. We show that in transfected mouse hair cells an USH1Bmutant GFP-myosin VIIa does not localize properly to inner ear hair cell stereocilia. However, a GFP-myosinVIIa protein engineered to have an equivalent DFNB2 mutation to p.E1716del localizes correctly in transfectedmouse hair cells. This finding is consistent with the hypothesis that p.E1716del causes a less severe phenotype(DFNB2) than the USH1B-associated alleles because the resulting protein retains some degree of normalfunction. Hum Mutat 0, 1–10, 2008.
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Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function.
Human mutation, 2008Co-Authors: Saima Riazuddin, Rehan S. Shaikh, Sabiha Nazli, Ahmed U Zafar, Farooq Sabar, Fareeha Zulfiqar, Shaheen N Khan, Zubair M Ahmed, Yi Yang, Fouzia T JavidAbstract:Recessive mutations of MYO7A, encoding unconventional myosin VIIA, can cause either a deaf-blindness syndrome (type 1 Usher syndrome; USH1B) or nonsyndromic deafness (DFNB2). In our study, deafness segregating as a recessive trait in 24 consanguineous families showed linkage to markers for the DFNB2/USH1B locus on chromosome 11q13.5. A total of 23 of these families segregate USH1 due to 17 homozygous mutant MYO7A alleles, of which 14 are novel. One family segregated nonsyndromic hearing loss DFNB2 due to a novel three-nucleotide deletion in an exon of MYO7A (p.E1716del) encoding a region of the tail domain. We hypothesized that DFNB2 alleles of MYO7A have residual myosin VIIA. To address this question we investigated the effects of several mutant alleles by making green fluorescent protein (GFP) tagged cDNA expression constructs containing engineered mutations of mouse MYO7A at codons equivalent to pathogenic USH1B and DFNB2 alleles of human MYO7A. We show that in transfected mouse hair cells an USH1B mutant GFP-myosin VIIa does not localize properly to inner ear hair cell stereocilia. However, a GFP-myosin VIIa protein engineered to have an equivalent DFNB2 mutation to p.E1716del localizes correctly in transfected mouse hair cells. This finding is consistent with the hypothesis that p.E1716del causes a less severe phenotype (DFNB2) than the USH1B-associated alleles because the resulting protein retains some degree of normal function.
Meredith L Weck - One of the best experts on this subject based on the ideXlab platform.
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structure of myo7b ush1c complex suggests a general pdz domain binding mode by myth4 ferm myosins
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Jianchao Li, Yunyun He, Meredith L Weck, Qing Lu, Matthew J Tyska, Mingjie ZhangAbstract: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.
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structure of myo7b ush1c complex suggests a general pdz domain binding mode by myth4 ferm myosins
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Meredith L Weck, Matthew J Tyska, Mingjie ZhangAbstract: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.
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impact of the motor and tail domains of class iii myosins on regulating the formation and elongation of actin protrusions
Journal of Biological Chemistry, 2016Co-Authors: Manmeet H Raval, Bechara Kachar, Omar A Quintero, Meredith L Weck, Matthew J Tyska, William C Unrath, James W Gallagher, Runjia Cui, Christopher M YengoAbstract:Abstract Class III myosins (MYO3A and MYO3B) are proposed to function as transporters as well as length and ultrastructure regulators within stable actin-based protrusions such as stereocilia and calycal processes. MYO3A differs from MYO3B in that it contains an extended tail domain with an additional actin-binding motif. We examined how the properties of the motor and tail domains of human class III myosins impact their ability to enhance the formation and elongation of actin protrusions. Direct examination of the motor and enzymatic properties of human MYO3A and MYO3B revealed that MYO3A is a 2-fold faster motor with enhanced ATPase activity and actin affinity. A chimera in which the MYO3A tail was fused to the MYO3B motor demonstrated that motor activity correlates with formation and elongation of actin protrusions. We demonstrate that removal of individual exons (30–34) in the MYO3A tail does not prevent filopodia tip localization but abolishes the ability to enhance actin protrusion formation and elongation in COS7 cells. Interestingly, our results demonstrate that MYO3A slows filopodia dynamics and enhances filopodia lifetime in COS7 cells. We also demonstrate that MYO3A is more efficient than MYO3B at increasing formation and elongation of stable microvilli on the surface of cultured epithelial cells. We propose that the unique features of MYO3A, enhanced motor activity, and an extended tail with tail actin-binding motif, allow it to play an important role in stable actin protrusion length and ultrastructure maintenance.
David S. Williams - One of the best experts on this subject based on the ideXlab platform.
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function of MYO7A in the human rpe and the validity of shaker1 mice as a model for usher syndrome 1b
Investigative Ophthalmology & Visual Science, 2010Co-Authors: Daniel Gibbs, Tanja Diemer, Kornnika Khanobdee, Jane Hu, David S. WilliamsAbstract:Usher syndrome is an autosomal recessive deaf-blindness disorder classified clinically by three subtypes. Usher syndrome type 1 is the most severe, with profound congenital deafness, followed by progressive retinal degeneration.1 Cochlear implants are now being used to correct the hearing of children with Usher 1,2 but there is no treatment of their ensuing blindness. Approximately half the cases of Usher 1 are classified as Usher 1B,3–5 which is caused by loss-of-function mutations in the MYO7A gene.6 Replacement gene therapy is a feasible approach to prevent retinal degeneration in Usher 1B. In a proof-of-principle study, it was shown that mutant retinal phenotypes in shaker1 mice could be corrected by the injection of lentiviral-MYO7A into the subretinal space.7 Although shaker1 mice carry mutations in the orthologue of the Usher 1B gene8,9 and those used in this gene therapy study carried a null allele of MYO7A,9–11 shaker1 mice do not undergo retinal degeneration.12 In this respect, they resemble murine models of other subtypes of Usher 113–16 but are in contrast to patients with Usher 1. Shaker1 mice do have a number of mutant retinal phenotypes, the clearest of which is the mislocalization and defective motility of melanosomes in the retinal pigment epithelium (RPE).17,18 These mutant phenotypes can be used to test the functionality of MYO7A that is expressed after gene therapy transduction of retinal cells.7 Nevertheless, these phenotypes have not been demonstrated in the retinas of patients with Usher 1B; hence, it is not clear how relevant they are to the human disease. In the present study, we tested whether primary cultures of human and mouse RPE cells were comparable with respect to MYO7A localization and MYO7A-related cell biology. In particular, we tested whether the human RPE cells exhibited the same MYO7A-dependent motility of melanosomes described for mouse RPE and, thus, whether defective melanosome localization and motility was a relevant phenotype for testing efficacy in preclinical animal studies of gene therapy for Usher 1B blindness.
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A novel allele of myosin VIIa reveals a critical function for the C-terminal FERM domain for melanosome transport in retinal pigment epithelial cells.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009Co-Authors: Martin Schwander, David S. Williams, Concepción Lillo, Daniel Gibbs, Vanda S. Lopes, Anna Sczaniecka, David L. Delano, Lisa M. Tarantino, Tim Wiltshire, Ulrich MüllerAbstract:Mutations in the head and tail domains of the motor protein myosin VIIA (MYO7A) cause deaf-blindness (Usher syndrome type 1B, USH1B) and nonsyndromic deafness (DFNB2, DFNA11). The head domain binds to F-actin and serves as the MYO7A motor domain, but little is known about the function of the tail domain. In a genetic screen, we have identified polka mice, which carry a mutation (c.5742 + 5G > A) that affects splicing of the MYO7A transcript and truncates the MYO7A tail domain at the C-terminal FERM domain. In the inner ear, expression of the truncated MYO7A protein is severely reduced, leading to defects in hair cell development. In retinal pigment epithelial (RPE) cells, the truncated MYO7A protein is expressed at comparative levels to wild-type protein but fails to associate with and transport melanosomes. We conclude that the C-terminal FERM domain of MYO7A is critical for melanosome transport in RPE cells. Our findings also suggest that MYO7A mutations can lead to tissue-specific effects on protein levels, which may explain why some mutations in MYO7A lead to deafness without retinal impairment.
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Analysis of the linkage of MYRIP and MYO7A to melanosomes by RAB27A in retinal pigment epithelial cells.
Cell motility and the cytoskeleton, 2007Co-Authors: Adriana E. Klomp, Karen Teofilo, Erin L. Legacki, David S. WilliamsAbstract:The apical region of the retinal pigment epithelium (RPE) typically contains melanosomes. Their apical distribution is dependent on RAB27A and the unconventional myosin, MYO7A. Evidence from studies using in vitro binding assays, melanocyte transfection, and immunolocalization have indicated that the exophilin, MYRIP, links RAB27A on melanosomes to MYO7A, analogous to the manner that melanophilin links RAB27A on melanocyte melanosomes to MYO5A. To test the functionality of this hypothesis in RPE cells, we have examined the relationship among MYRIP, RAB27A and MYO7A with studies of RPE cells in primary culture (including live-cell imaging), analyses of mutant mouse retinas, and RPE cell fractionation experiments. Our results indicate that the retinal distribution of MYRIP is limited to the RPE, mainly the apical region. In RPE cells, RAB27A, MYRIP, and MYO7A were all associated with melanosomes, undergoing both slow and rapid movements. Analyses of mutant mice provide genetic evidence that MYRIP is linked to melanosomes via RAB27A, but show that recruitment of MYRIP to apical RPE is independent of melanosomes and RAB27A. RAB27A and MYRIP also associated with motile small vesicles of unknown origin. The present results provide evidence from live RPE cells that the RAB27A-MYRIP-MYO7A complex functions in melanosome motility. They also demonstrate that RAB27A provides an essential link to the melanosome. Cell Motil. Cytoskeleton 2007. © 2007 Wiley-Liss, Inc.
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Physical and Functional Interaction between Protocadherin 15 and Myosin VIIa in Mechanosensory Hair Cells
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2006Co-Authors: Mathias Senften, Piotr Kazmierczak, Tama Hasson, David S. Williams, Martin Schwander, Concepción Lillo, Jung-bum Shin, Gwenaëlle S. G. Géléoc, Peter G. Gillespie, Jeffrey R. HoltAbstract:Hair cells of the mammalian inner ear are the mechanoreceptors that convert sound-induced vibrations into electrical signals. The molecular mechanisms that regulate the development and function of the mechanically sensitive organelle of hair cells, the hair bundle, are poorly defined. We link here two gene products that have been associated with deafness and hair bundle defects, protocadherin 15 (PCDH15) and myosin VIIa (MYO7A), into a common pathway. We show that PCDH15 binds to MYO7A and that both proteins are expressed in an overlapping pattern in hair bundles. PCDH15 localization is perturbed in MYO7A-deficient mice, whereas MYO7A localization is perturbed in PCDH15-deficient mice. Like MYO7A, PCDH15 is critical for the development of hair bundles in cochlear and vestibular hair cells, controlling hair bundle morphogenesis and polarity. Cochlear and vestibular hair cells from PCDH15-deficient mice also show defects in mechanotransduction. Together, our findings suggest that PCDH15 and MYO7A cooperate to regulate the development and function of the mechanically sensitive hair bundle.
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Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Daniel Gibbs, Junko Kitamoto, David S. WilliamsAbstract:Abstract Mutations in the myosin VIIa gene (MYO7A) cause Usher syndrome type 1B (USH1B), a major type of the deaf-blind disorder, Usher syndrome. We have studied mutant phenotypes in the retinas of MYO7A mutant mice (shaker1), with the aim of elucidating the role(s) of myosin VIIa in the retina and what might underlie photoreceptor degeneration in USH1B patients. A photoreceptor defect has been described. Here, we report that the phagocytosis of photoreceptor outer segment disks by the retinal pigment epithelium (RPE) is abnormal in MYO7A null mice. Both in vivo and in primary cultures of RPE cells, the transport of ingested disks out of the apical region is inhibited in the absence of MYO7A. The results with the cultured RPE cells were the same, irrespective of whether the disks came from wild-type or mutant mice, thus demonstrating that the RPE is the source of this defect. The inhibited transport seems to delay phagosome–lysosomal fusion, as the degradation of ingested disks was slower in mutant RPE. Moreover, fewer packets of disk membranes were ingested in vivo, possibly because retarded removal of phagosomes from the apical processes inhibited the ingestion of additional disk membranes. We conclude that MYO7A is required for the normal processing of ingested disk membranes in the RPE, primarily in the basal transport of phagosomes into the cell body where they then fuse with lysosomes. Because the phagocytosis of photoreceptor disks by the RPE has been shown to be critical for photoreceptor cell viability, this defect likely contributes to the progressive blindness in USH1B.
