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Manabu Yoshida - One of the best experts on this subject based on the ideXlab platform.
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valosin containing Protein P97 interacts with sperm activating and sperm attracting factor saaf in the ascidian egg and modulates sperm attracting activity
Development Growth & Differentiation, 2008Co-Authors: Eri Kondoh, Aru Konno, Kazuo Inaba, Tohru Oishi, Michio Murata, Manabu YoshidaAbstract:Sperm chemotaxis toward an egg is observed in many animals, and the control of sperm-attracting activity is thought to play an important role in ensuring fertilization. However, the mechanism underlying the release of a sperm attractant from an egg is still obscure. In this study, we examined the systems involved in the release of sperm-activating and sperm-attracting factor (SAAF), which is the sperm attractant of the ascidian Ciona intestinalis. Here, we show that the egg acquires sperm-attracting activity after germinal vesicle breakdown. Further, since the cytoplasmic extracts of immature oocytes exhibit no sperm-attracting activity, the SAAF in oocytes may be activated after germinal vesicle breakdown. We found 13 SAAF-binding Proteins in an egg plasma membrane extract and identified five Proteins by proteomic analysis: valosin-containing Protein (VCP)/P97, proteasome alpha 2 subunit, MGC97756 Protein, proteasome subunit Y, and beta-tubulin. In particular, the interaction between VCP/P97 and SAAF was confirmed by a pull-down assay. VCP/P97 is initially localized in the germinal vesicle, and during oocyte maturation, it shifts to the endoplasmic reticulum in the cortical regions. Thus, VCP/P97 is a potential modulator of SAAF release from the egg.
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Valosin-containing Protein/P97 interacts with sperm-activating and sperm-attracting factor (SAAF) in the ascidian egg and modulates sperm-attracting activity.
Development growth & differentiation, 2008Co-Authors: Eri Kondoh, Aru Konno, Kazuo Inaba, Tohru Oishi, Michio Murata, Manabu YoshidaAbstract:Sperm chemotaxis toward an egg is observed in many animals, and the control of sperm-attracting activity is thought to play an important role in ensuring fertilization. However, the mechanism underlying the release of a sperm attractant from an egg is still obscure. In this study, we examined the systems involved in the release of sperm-activating and sperm-attracting factor (SAAF), which is the sperm attractant of the ascidian Ciona intestinalis. Here, we show that the egg acquires sperm-attracting activity after germinal vesicle breakdown. Further, since the cytoplasmic extracts of immature oocytes exhibit no sperm-attracting activity, the SAAF in oocytes may be activated after germinal vesicle breakdown. We found 13 SAAF-binding Proteins in an egg plasma membrane extract and identified five Proteins by proteomic analysis: valosin-containing Protein (VCP)/P97, proteasome alpha 2 subunit, MGC97756 Protein, proteasome subunit Y, and beta-tubulin. In particular, the interaction between VCP/P97 and SAAF was confirmed by a pull-down assay. VCP/P97 is initially localized in the germinal vesicle, and during oocyte maturation, it shifts to the endoplasmic reticulum in the cortical regions. Thus, VCP/P97 is a potential modulator of SAAF release from the egg.
Paul S. Freemont - One of the best experts on this subject based on the ideXlab platform.
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the n terminal region of the ubiquitin regulatory x ubx domain containing Protein 1 ubxd1 modulates interdomain communication within the valosin containing Protein P97
Journal of Biological Chemistry, 2015Co-Authors: Franziska Trusch, Anja Matena, Lisa Koerver, Helene Knaevelsrud, Hemmo Meyer, Paul S. Freemont, Peter BayerAbstract:Valosin-containing Protein/P97 is an ATP-driven Protein segregase that cooperates with distinct Protein cofactors to control various aspects of cellular homeostasis. Mutations at the interface between the regulatory N-domain and the first of two ATPase domains (D1 and D2) deregulate the ATPase activity and cause a multisystem degenerative disorder, inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia/amyotrophic lateral sclerosis. Intriguingly, the mutations affect only a subset of P97-mediated pathways correlating with unbalanced cofactor interactions and most prominently compromised binding of the ubiquitin regulatory X domain-containing Protein 1 (UBXD1) cofactor during endolysosomal sorting of caveolin-1. However, how the mutations impinge on the P97-cofactor interplay is unclear so far. In cell-based endosomal localization studies, we identified a critical role of the N-terminal region of UBXD1 (UBXD1-N). Biophysical studies using NMR and CD spectroscopy revealed that UBXD1-N can be classified as intrinsically disordered. NMR titration experiments confirmed a valosin-containing Protein/P97 interaction motif and identified a second binding site at helices 1 and 2 of UBXD1-N as binding interfaces for P97. In reverse titration experiments, we identified two distant epitopes on the P97 N-domain that include disease-associated residues and an additional interaction between UBXD1-N and the D1D2 barrel of P97 that was confirmed by fluorescence anisotropy. Functionally, binding of UBXD1-N to P97 led to a reduction of ATPase activity and partial protection from proteolysis. These findings indicate that UBXD1-N intercalates into the P97-ND1 interface, thereby modulating interdomain communication of P97 domains and its activity with relevance for disease pathogenesis. We propose that the polyvalent binding mode characterized for UBXD1-N is a more general principle that defines a subset of P97 cofactors.
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Inter-ring rotations of AAA ATPase P97 revealed by electron cryomicroscopy
Open biology, 2014Co-Authors: Heidi O. Yeung, Hajime Niwa, Xiaodong Zhang, Andreas Förster, Cecilia Bebeacua, Caroline A. Ewens, Ciaran Mckeown, Paul S. FreemontAbstract:The type II AAA+ Protein P97 is involved in numerous cellular activities, including endoplasmic reticulum-associated degradation, transcription activation, membrane fusion and cell-cycle control. These activities are at least in part regulated by the ubiquitin system, in which P97 is thought to target ubiquitylated Protein substrates within macromolecular complexes and assist in their extraction or disassembly. Although ATPase activity is essential for P97 function, little is known about how ATP binding or hydrolysis is coupled with P97 conformational changes and substrate remodelling. Here, we have used single-particle electron cryomicroscopy (cryo-EM) to study the effect of nucleotides on P97 conformation. We have identified conformational heterogeneity within the cryo-EM datasets from which we have resolved two major P97 conformations. A comparison of conformations reveals inter-ring rotations upon nucleotide binding and hydrolysis that may be linked to the remodelling of target Protein complexes.
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Regulation of P97 in the ubiquitin-proteasome system by the UBX Protein-family.
Biochimica et biophysica acta, 2011Co-Authors: Patrik Kloppsteck, Xiaodong Zhang, Andreas Förster, Caroline A. Ewens, Paul S. FreemontAbstract:Abstract The AAA Protein P97 is a central component in the ubiquitin–proteasome system, in which it is thought to act as a molecular chaperone, guiding Protein substrates to the 26S proteasome for degradation. This function is dependent on association with cofactors that are specific to the different biological pathways P97 participates in. The UBX-Protein family (ubiquitin regulatory X) constitutes the largest known group of P97 cofactors. We propose that the regulation of P97 by UBX-Proteins utilizes conserved structural features of this family. Firstly, they act as scaffolding subunits in P97-containing multiProtein complexes, by providing additional interaction motifs. Secondly, they provide regulation of multiProtein complex assembly and we suggest two possible models for P97 substrate recruitment in the UPS pathway. Lastly, they impose constraints on P97 and its interaction with substrates and further cofactors. These features allow the regulation, within the UPS, of the competitive interactions on P97, a regulation that is crucial to allow the diverse functionality of P97. This article is part of a Special Issue entitled: AAA ATPases: structure and function.
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Insights into adaptor binding to the AAA Protein P97
Biochemical Society Transactions, 2008Co-Authors: Heidi O. Yeung, Patrik Kloppsteck, Hajime Niwa, Rivka L. Isaacson, Steve Matthews, Xiaodong Zhang, Paul S. FreemontAbstract:The AAA (ATPase associated with various cellular activities) P97 [also known as VCP (valosin-containing Protein)] participates in numerous biological activities and is an essential component of the ubiquitin signalling pathway. A plethora of adaptors have been reported for P97, and increasing evidence is suggesting that it is through adaptor binding that P97 is diverted into different cellular pathways. Studying the interaction between P97 and its adaptors is therefore crucial to our understanding of the physiological roles of the Protein. The interactions between P97 and the PUB [PNGase (peptide N-glycosidase)/ubiquitin-associated] domain of PNGase, the UBX (ubiquitin regulatory X) domain of p47, and the UBD (ubiquitin D) domain of Npl4 have been structurally characterized. UBX and UBD are structural homologues that share similar P97-binding modes; it is plausible that other Proteins that contain a UBX/UBX-like domain also interact with P97 via similar mechanisms. In addition, several short P97-interacting motifs, such as VBM (VCP-binding motif), VIM (VCP-interacting motif) and SHP, have been identified recently and are also shared between P97 adaptors, hinting that Proteins possessing the same P97-binding motif might also share common P97-binding mechanisms. In this review, we aim to summarize our current knowledge on adaptor binding to P97.
Eri Kondoh - One of the best experts on this subject based on the ideXlab platform.
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valosin containing Protein P97 interacts with sperm activating and sperm attracting factor saaf in the ascidian egg and modulates sperm attracting activity
Development Growth & Differentiation, 2008Co-Authors: Eri Kondoh, Aru Konno, Kazuo Inaba, Tohru Oishi, Michio Murata, Manabu YoshidaAbstract:Sperm chemotaxis toward an egg is observed in many animals, and the control of sperm-attracting activity is thought to play an important role in ensuring fertilization. However, the mechanism underlying the release of a sperm attractant from an egg is still obscure. In this study, we examined the systems involved in the release of sperm-activating and sperm-attracting factor (SAAF), which is the sperm attractant of the ascidian Ciona intestinalis. Here, we show that the egg acquires sperm-attracting activity after germinal vesicle breakdown. Further, since the cytoplasmic extracts of immature oocytes exhibit no sperm-attracting activity, the SAAF in oocytes may be activated after germinal vesicle breakdown. We found 13 SAAF-binding Proteins in an egg plasma membrane extract and identified five Proteins by proteomic analysis: valosin-containing Protein (VCP)/P97, proteasome alpha 2 subunit, MGC97756 Protein, proteasome subunit Y, and beta-tubulin. In particular, the interaction between VCP/P97 and SAAF was confirmed by a pull-down assay. VCP/P97 is initially localized in the germinal vesicle, and during oocyte maturation, it shifts to the endoplasmic reticulum in the cortical regions. Thus, VCP/P97 is a potential modulator of SAAF release from the egg.
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Valosin-containing Protein/P97 interacts with sperm-activating and sperm-attracting factor (SAAF) in the ascidian egg and modulates sperm-attracting activity.
Development growth & differentiation, 2008Co-Authors: Eri Kondoh, Aru Konno, Kazuo Inaba, Tohru Oishi, Michio Murata, Manabu YoshidaAbstract:Sperm chemotaxis toward an egg is observed in many animals, and the control of sperm-attracting activity is thought to play an important role in ensuring fertilization. However, the mechanism underlying the release of a sperm attractant from an egg is still obscure. In this study, we examined the systems involved in the release of sperm-activating and sperm-attracting factor (SAAF), which is the sperm attractant of the ascidian Ciona intestinalis. Here, we show that the egg acquires sperm-attracting activity after germinal vesicle breakdown. Further, since the cytoplasmic extracts of immature oocytes exhibit no sperm-attracting activity, the SAAF in oocytes may be activated after germinal vesicle breakdown. We found 13 SAAF-binding Proteins in an egg plasma membrane extract and identified five Proteins by proteomic analysis: valosin-containing Protein (VCP)/P97, proteasome alpha 2 subunit, MGC97756 Protein, proteasome subunit Y, and beta-tubulin. In particular, the interaction between VCP/P97 and SAAF was confirmed by a pull-down assay. VCP/P97 is initially localized in the germinal vesicle, and during oocyte maturation, it shifts to the endoplasmic reticulum in the cortical regions. Thus, VCP/P97 is a potential modulator of SAAF release from the egg.
Masayuki Komada - One of the best experts on this subject based on the ideXlab platform.
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the ankrd13 family of ubiquitin interacting motif bearing Proteins regulates valosin containing Protein P97 Protein mediated lysosomal trafficking of caveolin 1
Journal of Biological Chemistry, 2016Co-Authors: Daocharad Burana, Keiji Tanaka, Hidehito Yoshihara, Hidetaka Tanno, Akitsugu Yamamoto, Yasushi Saeki, Masayuki KomadaAbstract:Caveolin 1 (Cav-1) is an oligomeric Protein that forms flask-shaped, lipid-rich pits, termed caveolae, on the plasma membrane. Cav-1 is targeted for lysosomal degradation in ubiquitination- and valosin-containing Protein (VCP)-dependent manners. VCP, an ATPase associated with diverse cellular activities that remodels or segregates ubiquitinated Protein complexes, has been proposed to disassemble Cav-1 oligomers on the endosomal membrane, facilitating the trafficking of Cav-1 to the lysosome. Genetic mutations in VCP compromise the lysosomal trafficking of Cav-1, leading to a disease called inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia (IBMPFD). Here we identified the Ankrd13 family of ubiquitin-interacting motif (UIM)-containing Proteins as novel VCP-interacting molecules on the endosome. Ankrd13 Proteins formed a ternary complex with VCP and Cav-1 and exhibited high binding affinity for ubiquitinated Cav-1 oligomers in an UIM-dependent manner. Mass spectrometric analyses revealed that Cav-1 undergoes Lys-63-linked polyubiquitination, which serves as a lysosomal trafficking signal, and that the UIMs of Ankrd13 Proteins bind preferentially to this ubiquitin chain type. The overexpression of Ankrd13 caused enlarged hollow late endosomes, which was reminiscent of the phenotype of the VCP mutations in IBMPFD. Overexpression of Ankrd13 Proteins also stabilized ubiquitinated Cav-1 oligomers on the limiting membrane of enlarged endosomes. The interaction with Ankrd13 was abrogated in IMBPFD-associated VCP mutants. Collectively, our results suggest that Ankrd13 Proteins cooperate with VCP to regulate the lysosomal trafficking of ubiquitinated Cav-1.
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The Ankrd13 Family of Ubiquitin-interacting Motif-bearing Proteins Regulates Valosin-containing Protein/P97 Protein-mediated Lysosomal Trafficking of Caveolin 1.
The Journal of biological chemistry, 2016Co-Authors: Daocharad Burana, Keiji Tanaka, Hidehito Yoshihara, Hidetaka Tanno, Akitsugu Yamamoto, Yasushi Saeki, Masayuki KomadaAbstract:Caveolin 1 (Cav-1) is an oligomeric Protein that forms flask-shaped, lipid-rich pits, termed caveolae, on the plasma membrane. Cav-1 is targeted for lysosomal degradation in ubiquitination- and valosin-containing Protein (VCP)-dependent manners. VCP, an ATPase associated with diverse cellular activities that remodels or segregates ubiquitinated Protein complexes, has been proposed to disassemble Cav-1 oligomers on the endosomal membrane, facilitating the trafficking of Cav-1 to the lysosome. Genetic mutations in VCP compromise the lysosomal trafficking of Cav-1, leading to a disease called inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia (IBMPFD). Here we identified the Ankrd13 family of ubiquitin-interacting motif (UIM)-containing Proteins as novel VCP-interacting molecules on the endosome. Ankrd13 Proteins formed a ternary complex with VCP and Cav-1 and exhibited high binding affinity for ubiquitinated Cav-1 oligomers in an UIM-dependent manner. Mass spectrometric analyses revealed that Cav-1 undergoes Lys-63-linked polyubiquitination, which serves as a lysosomal trafficking signal, and that the UIMs of Ankrd13 Proteins bind preferentially to this ubiquitin chain type. The overexpression of Ankrd13 caused enlarged hollow late endosomes, which was reminiscent of the phenotype of the VCP mutations in IBMPFD. Overexpression of Ankrd13 Proteins also stabilized ubiquitinated Cav-1 oligomers on the limiting membrane of enlarged endosomes. The interaction with Ankrd13 was abrogated in IMBPFD-associated VCP mutants. Collectively, our results suggest that Ankrd13 Proteins cooperate with VCP to regulate the lysosomal trafficking of ubiquitinated Cav-1.
Yi-ping Hsueh - One of the best experts on this subject based on the ideXlab platform.
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From neurodevelopment to neurodegeneration: the interaction of neurofibromin and valosin-containing Protein/P97 in regulation of dendritic spine formation
Journal of biomedical science, 2012Co-Authors: Yi-ping HsuehAbstract:Both Neurofibromatosis type I (NF1) and inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) are autosomal dominant genetic disorders. These two diseases are fully penetrant but with high heterogeneity in phenotypes, suggesting the involvement of genetic modifiers in modulating patients' phenotypes. Although NF1 is recognized as a developmental disorder and IBMPFD is associated with degeneration of multiple tissues, a recent study discovered the direct Protein interaction between neurofibromin, the Protein product of the NF1 gene, and VCP/P97, encoded by the causative gene of IBMPFD. Both NF1 and VCP/P97 are critical for dendritic spine formation, which provides the cellular mechanism explaining the cognitive deficits and dementia found in patients. Moreover, disruption of the interaction between neurofibromin and VCP impairs dendritic spinogenesis. Neurofibromin likely influences multiple downstream pathways to control dendritic spinogenesis. One is to activate the Protein kinase A pathway to initiate dendritic spine formation; another is to regulate the synaptic distribution of VCP and control the activity of VCP in dendritic spinogenesis. Since neurofibromin and VCP/P97 also regulate cell growth and bone metabolism, the understanding of neurofibromin and VCP/P97 in neurons may be applied to study of cancer and bone. Statin treatment rescues the spine defects caused by VCP deficiency, suggesting the potential role of statin in clinical treatment for these two diseases.
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from neurodevelopment to neurodegeneration the interaction of neurofibromin and valosin containing Protein P97 in regulation of dendritic spine formation
Journal of Biomedical Science, 2012Co-Authors: Yi-ping HsuehAbstract:Both Neurofibromatosis type I (NF1) and inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) are autosomal dominant genetic disorders. These two diseases are fully penetrant but with high heterogeneity in phenotypes, suggesting the involvement of genetic modifiers in modulating patients' phenotypes. Although NF1 is recognized as a developmental disorder and IBMPFD is associated with degeneration of multiple tissues, a recent study discovered the direct Protein interaction between neurofibromin, the Protein product of the NF1 gene, and VCP/P97, encoded by the causative gene of IBMPFD. Both NF1 and VCP/P97 are critical for dendritic spine formation, which provides the cellular mechanism explaining the cognitive deficits and dementia found in patients. Moreover, disruption of the interaction between neurofibromin and VCP impairs dendritic spinogenesis. Neurofibromin likely influences multiple downstream pathways to control dendritic spinogenesis. One is to activate the Protein kinase A pathway to initiate dendritic spine formation; another is to regulate the synaptic distribution of VCP and control the activity of VCP in dendritic spinogenesis. Since neurofibromin and VCP/P97 also regulate cell growth and bone metabolism, the understanding of neurofibromin and VCP/P97 in neurons may be applied to study of cancer and bone. Statin treatment rescues the spine defects caused by VCP deficiency, suggesting the potential role of statin in clinical treatment for these two diseases.
