Crystal Structure of Human Myosin 1c—The Motor in GLUT4 Exocytosis: Implications for Ca2+ Regulation and 14-3-3 Binding

Münnich, Stefan; Taft, Manuel H.; Manstein, Dietmar J.

doi:10.1016/j.jmb.2014.03.004

Cited by 48 publications

(54 citation statements)

References 45 publications

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“…9 In addition, MYO1C is recruited onto highly dynamic lipid-raft enriched membrane tubules in the endocytic recycling pathway, where it is required for delivery and exocytosis of lipidraft enriched membranes at the plasma membrane. 6,10 This function is supported by the finding that MYO1C facilitates the exocytosis and delivery of several raftassociated cargoes such as SLC2A4/GLUT4, 11,12 AQP2/aquaporin 2, 13 KIRREL/NEPH1 14 as well as KDR/VEGFR2 15 to the cell surface. At the cellular level, ablating MYO1C function results in a redistribution of lipid-raft enriched domains from the plasma membrane to intracellular compartments and an accumulation of these membranes in the perinuclear region.…”

Section: Introductionmentioning

confidence: 88%

Loss of functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion

et al. 2014

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Abbreviations: BafA 1 , bafilomycin A 1 ; EM, electron microscopy; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; GFP, green fluorescent protein; KD, knockdown; LAMP1, lysosomal-associated membrane protein 1; LC3, microtubuleassociated protein 1 light chain 3; MYO1C, myosin IC; MVB, multivesicular body; PB, phosphate buffer; PCIP, pentachloropseudilin; PtdIns(4, 5)P 2 , phosphatidylinositol 4, 5-bisphosphate; RFP, red fluorescent protein; RPE, retinal pigment epithelium.MYO1C, a single-headed class I myosin, associates with cholesterol-enriched lipid rafts and facilitates their recycling from intracellular compartments to the cell surface. Absence of functional MYO1C disturbs the cellular distribution of lipid rafts, causes the accumulation of cholesterol-enriched membranes in the perinuclear recycling compartment, and leads to enlargement of endolysosomal membranes. Several feeder pathways, including classical endocytosis but also the autophagy pathway, maintain the health of the cell by selective degradation of cargo through fusion with the lysosome. Here we show that loss of functional MYO1C leads to an increase in total cellular cholesterol and its disrupted subcellular distribution. We observe an accumulation of autophagic structures caused by a block in fusion with the lysosome and a defect in autophagic cargo degradation. Interestingly, the loss of MYO1C has no effect on degradation of endocytic cargo such as EGFR, illustrating that although the endolysosomal compartment is enlarged in size, it is functional, contains active hydrolases, and the correct pH. Our results highlight the importance of correct lipid composition in autophagosomes and lysosomes to enable them to fuse. Ablating MYO1C function causes abnormal cholesterol distribution, which has a major selective impact on the autophagy pathway.

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Section: Introductionmentioning

confidence: 88%

Loss of functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion

et al. 2014

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“…The LCs stabilize the ␣-helical structure of the LCBD, allowing it to function as a rigid swinging lever arm to amplify ATP-dependent conformational changes that originate within the motor domain (19). The LCs are also important regulatory sites that interact with the motor domain to influence mechanochemical properties such as step size, motility rate, and force sensing (1,20,21).The social amoeba Dictyostelium discoideum has been used extensively to study myosin-1 structure, function, and regulation. The seven Dictyostelium myosin-1 isozymes include three with short tails that contain only a TH1 domain (myosin-1A, -1E, and -1F), three with long tails that have TH1, TH2, and Src homology 3 domains (myosin-1B, -1C, and -1D), and one with no tail (myosin-1K) (22).…”

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confidence: 99%

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confidence: 99%

Structure of the Single-lobe Myosin Light Chain C in Complex with the Light Chain-binding Domains of Myosin-1C Provides Insights into Divergent IQ Motif Recognition

Langelaan¹,

Liburd²,

Yang

et al. 2016

Journal of Biological Chemistry

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Myosin light chains are key regulators of class 1 myosins and typically comprise two domains, with calmodulin being the archetypal example. They bind IQ motifs within the myosin neck region and amplify conformational changes in the motor domain. A single lobe light chain, myosin light chain C (MlcC), was recently identified and shown to specifically bind to two sequentially divergent IQ motifs of the Dictyostelium myosin-1C. To provide a molecular basis of this interaction, the structures of apo-MlcC and a 2:1 MlcC⅐myosin-1C neck complex were determined. The two non-functional EF-hand motifs of MlcC pack together to form a globular four-helix bundle that opens up to expose a central hydrophobic groove, which interacts with the N-terminal portion of the divergent IQ1 and IQ2 motifs. The N-and C-terminal regions of MlcC make critical contacts that contribute to its specific interactions with the myosin-1C divergent IQ motifs, which are contacts that deviate from the traditional mode of calmodulin-IQ recognition.The class 1 myosins (myosin-1) are a widely expressed family of single-headed, non-filament-forming, membrane-binding myosins (1-3). The myosin-1 heavy chain consists of a highly conserved N-terminal motor domain with sites for binding actin and for ATP hydrolysis, a light chain-binding domain (LCBD) 5 that acts as the motor's lever arm, and a C-terminal tail. The myosin-1 tail contains a tail homology 1 (TH1) domain that interacts with acidic phospholipids and, in some cases, also contains a glycine-and proline-rich TH2 domain that binds filamentous actin and an Src homology 3 domain that forms complexes with proteins that stimulate actin filament assembly (4 -10). Myosin-1 is able to cross-link the plasma membrane to the underlying actin cytoskeleton and plays a direct role in the control of cortical and membrane tension (11,12). These motor proteins can also drive vesicle trafficking, pseudopod retraction, and the uptake of particles and fluids by phagocytosis and micropinocytosis (13-16).The myosin-1 LCBD includes one or more IQ motifs, which are ␣-helical sequences between 18 and 25 residues in length that terminate with a loosely conserved IQXXXRGXXXR consensus sequence (17, 18). IQ motifs bind calmodulin (CaM) or CaM-related light chains (LCs) in the absence of Ca 2ϩ . The LCs stabilize the ␣-helical structure of the LCBD, allowing it to function as a rigid swinging lever arm to amplify ATP-dependent conformational changes that originate within the motor domain (19). The LCs are also important regulatory sites that interact with the motor domain to influence mechanochemical properties such as step size, motility rate, and force sensing (1,20,21).The social amoeba Dictyostelium discoideum has been used extensively to study myosin-1 structure, function, and regulation. The seven Dictyostelium myosin-1 isozymes include three with short tails that contain only a TH1 domain (myosin-1A, -1E, and -1F), three with long tails that have TH1, TH2, and Src homology 3 domains (myosin-1B, -1C, and -1D), and one ...

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“…To compare the shape of the SAXS-based model with other complementary information, a structural model of full-length Myo1c was generated bound to three calmodulins on its IQ domain. In brief, the SWISS-MODEL server was used to stitch together the individual crystal structures of the Myo1c head (Protein Data Bank [PDB] code 4BYF) and tail (PDB code 4R8G) regions, both in complex with calmodulin (32,34,44). The two structures had common IQ domains which were used for relative referencing of the other domains' coordinates.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, crystal structures of the Myo1c head domain bound to calmodulin (32,33) and the Myo1c tail bound to calmodulin (34) were reported. Although these studies provided significant insight into the conformation of Myo1c, they analyzed only partial Myo1c structures.…”

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confidence: 99%

Structural Analysis of the Myo1c and Neph1 Complex Provides Insight into the Intracellular Movement of Neph1

Arif

Sharma

Solanki

et al. 2016

Molecular and Cellular Biology

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The Myo1c motor functions as a cargo transporter supporting various cellular events, including vesicular trafficking, cell migration, and stereociliary movements of hair cells. Although its partial crystal structures were recently described, the structural details of its interaction with cargo proteins remain unknown. This study presents the first structural demonstration of a cargo protein, Neph1, attached to Myo1c, providing novel insights into the role of Myo1c

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Crystal Structure of Human Myosin 1c—The Motor in GLUT4 Exocytosis: Implications for Ca2+ Regulation and 14-3-3 Binding

Cited by 48 publications

References 45 publications

Loss of functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion

Loss of functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion

Structure of the Single-lobe Myosin Light Chain C in Complex with the Light Chain-binding Domains of Myosin-1C Provides Insights into Divergent IQ Motif Recognition

Structural Analysis of the Myo1c and Neph1 Complex Provides Insight into the Intracellular Movement of Neph1

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