Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.4.4 (kinesin)
5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Puralpha, which is involved in diverse aspects of cellular functions, is strongly expressed in neuronal cytoplasm. Previously, we have reported that this protein controls BC1 RNA expression and its subsequent distribution within dendrites and that Puralpha is associated with polyribosomes. Here, we report that, following treatment with EDTA, Puralpha was released from polyribosomes in mRNA/protein complexes (mRNPs), which also contained mStaufen, Fragile X Mental Retardation Protein (FMRP), myosin Va, and other proteins with unknown functions. As the coimmunoprecipitation of these proteins by an anti-Puralpha antibody was abolished by RNase treatment, Puralpha may assist mRNP assembly in an RNA-dependent manner and be involved in targeting mRNPs to polyribosomes in cooperation with other RNA-binding proteins. The immunoprecipitation of mStaufen- and FMRP-containing mRNPs provided additional evidence that the anti-Puralpha detected structurally or functionally related mRNA subsets, which are distributed in the somatodendritic compartment. Furthermore, mRNPs appear to reside on rough endoplasmic reticulum equipped with a kinesin motor. Based on our present findings, we propose that this rough endoplasmic reticulum structure may form the molecular machinery that mediates and regulates multistep transport of polyribosomes along microtubules and actin filaments, as well as localized translation in the somatodendritic compartment.
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PMID:Identification of mRNA/protein (mRNP) complexes containing Puralpha, mStaufen, fragile X protein, and myosin Va and their association with rough endoplasmic reticulum equipped with a kinesin motor. 1214 88

Using a novel assay based on the sorting and transport of a fluorescent fragment of tetanus toxin, we have investigated the cytoskeletal and motor requirements of axonal retrograde transport in living mammalian motor neurons. This essential process ensures the movement of neurotrophins and organelles from the periphery to the cell body and is crucial for neuronal survival. Unlike what is observed in sympathetic neurons, fast retrograde transport in motor neurons requires not only intact microtubules, but also actin microfilaments. Here, we show that the movement of tetanus toxin-containing carriers relies on the nonredundant activities of dynein as well as kinesin family members. Quantitative kinetic analysis indicates a role for dynein as the main motor of these carriers. Moreover, this approach suggests the involvement of myosin(s) in retrograde movement. Immunofluorescence screening with isoform-specific myosin antibodies reveals colocalization of tetanus toxin-containing retrograde carriers with myosin Va. Motor neurons from homozygous myosin Va null mice showed slower retrograde transport compared with wild-type cells, establishing a unique role for myosin Va in this process. On the basis of our findings, we propose that coordination of myosin Va and microtubule-dependent motors is required for fast axonal retrograde transport in motor neurons.
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PMID:Myosin Va and microtubule-based motors are required for fast axonal retrograde transport of tetanus toxin in motor neurons. 1457 57

Melanosomes are lysosome-related organelles within which melanin pigment is synthesized. The molecular motors that allow these organelles to move within melanocytes have been the subject of intense study in several organisms. In mammals, melanosomes travel bi-directionally along microtubule tracks. The anterograde movement, i.e., towards microtubule plus-ends at the periphery, is accomplished by proteins of the kinesin superfamily, whereas the retrograde movement, i.e., towards microtubule minus-ends at the cell center, is achieved by dynein and dynein-associated proteins. At the periphery, melanosomes interact with the actin cytoskeleton via a tripartite complex formed by the small GTPase Rab27a, melanophilin and myosin Va, an actin-based motor. This interaction is essential for the maintenance of a dispersed state of the melanosomes, as shown by the perinuclear clustering of organelles in mutants in any of the referred proteins. In the retinal pigment epithelium, a similar complex formed by Rab27a, a melanophilin homolog called MyRIP and myosin VIIa is probably responsible for the tethering of melanosomes to the actin cytoskeleton. The coordination of motor activities is still poorly characterized, although some models have emerged in recent years and are discussed here. Unraveling regulatory mechanisms responsible for melanosome motility in pigmented cells will provide general insights into organelles dynamics within eukaryotic cells.
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PMID:The melanosome as a model to study organelle motility in mammals. 1501 99

Periaxoplasmic ribosomal plaques (PARPs) are discrete ribosome-containing domains distributed intermittently along the periphery of axoplasm in myelinated fibers. Thus, they are structural formations in which translational machinery is spatially organized to serve as centers of protein synthesis for local metabolic requirements and perhaps repair as well. Because of evidence that RNA is transported to putative PARP domains, involving both microtubule- and actin-based mechanisms, it was of interest to investigate whether cytoskeletal motor proteins exhibit a nonrandom localization within PARP domains. Axoplasm, from large Mauthner fibers and rat or rabbit spinal ventral nerve root fibers, removed from the myelin sheath in the form of an "axoplasmic whole-mount" was used for this analysis. PARP domains were identified either by specific immunofluorescence of rRNA, ribosomal P antigen, or by nonspecific RNA fluorescence using RNA binding dyes YOYO-1 or POPO-1. A polyclonal antibody (pAb) against the motor domain of myosin Va showed prominent nonrandom immunofluorescence labeling in PARP domains. Similarly, monoclonal antibodies (mAb) against kinesin KIF3A and a pan-specific antikinesin (mAb IBII) also showed a preponderant immunofluorescence in PARP domains. On the other hand, H2, a mAb antikinesin KIF5A, exhibited only random immunofluorescence labeling in axoplasm, as was also the case with pAb antidynein heavy chain immunofluorescence. Several possible explanations for these findings are considered, primary among which is targeted trafficking of translational machinery that results in local accumulation of motor proteins. Additional possibilities are trafficking functions intrinsic to the domain, and/or functions that govern dynamic organizational properties of PARPs.
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PMID:Myosin Va and kinesin II motor proteins are concentrated in ribosomal domains (periaxoplasmic ribosomal plaques) of myelinated axons. 1526 50

Certain types of intracellular organelle transport to the cell periphery are thought to involve long-range movement on microtubules by kinesin with subsequent handoff to vertebrate myosin Va (myoVa) for local delivery on actin tracks. This process may involve direct interactions between these two processive motors. Here we demonstrate using single molecule in vitro techniques that myoVa is flexible enough to effectively maneuver its way through actin filament intersections and Arp2/3 branches. In addition, myoVa surprisingly undergoes a one-dimensional diffusive search along microtubules, which may allow it to scan efficiently for kinesin and/or its cargo. These features of myoVa may help ensure efficient cargo delivery from the cell center to the periphery.
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PMID:Myosin Va maneuvers through actin intersections and diffuses along microtubules. 1737 17

Matrix metalloproteinases (MMPs) are endopeptidases that cleave matrix, soluble and membrane-bound proteins and are regulated by their endogenous inhibitors the tissue inhibitors of MMPs (TIMPs). Nothing is known about MMP/TIMP trafficking and secretion in neuronal cells. We focussed our attention on the gelatinases MMP-2 and MMP-9, and their inhibitor TIMP-1. MMPs and TIMP-1 fused to GFP were expressed in N2a neuroblastoma and primary neuronal cells to study trafficking and secretion using real time video-microscopy, imaging, electron microscopy and biochemical approaches. We show that MMPs and TIMP-1 are secreted in 160-200 nm vesicles in a Golgi-dependent pathway. These vesicles distribute along microtubules and microfilaments, co-localise differentially with the molecular motors kinesin and myosin Va and undergo both anterograde and retrograde trafficking. MMP-9 retrograde transport involves the dynein/dynactin molecular motor. In hippocampal neurons, MMP-2 and MMP-9 vesicles are preferentially distributed in the somato-dendritic compartment and are found in dendritic spines. Non-transfected hippocampal neurons also demonstrate vesicular secretion of MMP-2 in both its pro- and active forms and gelatinolytic activity localised within dendritic spines. Our results show differential trafficking of MMP and TIMP-1-containing vesicles in neuronal cells and suggest that these vesicles could play a role in neuronal and synaptic plasticity.
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PMID:Vesicular trafficking and secretion of matrix metalloproteinases-2, -9 and tissue inhibitor of metalloproteinases-1 in neuronal cells. 1881 73

Periaxoplasmic ribosomal plaques (PARPs) are systematically recurring ribosome-containing structural domains located in the F-actin-rich periphery of axoplasm in myelinated fibers. In contrast, endoaxoplasmic ribosomal plaques (EARPs) are small, oval-shaped ribosomal aggregate structures randomly dispersed within the axoplasm of unmyelinated squid giant axons. Ribosomes are attached to a superficial plaque-like structural matrix, which "caps" the domain at the outer cortical margin and appears fragmented in subcortical axoplasm. As such, the matrix represents a novel hallmark of PARP domains. Molecular markers concentrated in PARP domains include beta-actin mRNA, ZBP-1, SRP54, myosin Va and kinesin II molecular motor proteins. Rapid axoplasmic transport of microinjected heterologous radiolabeled BC1 RNA to putative PARP domains, mediated pari passu by microtubule- and F-actin-dependent systems, suggests that translation machinery, anchored by the matrix could provide targeted destinations for RNA trafficking. As distributed local centers of protein synthesis along axons, PARPs are likely to share modes of expression in common with other translational subdomains in neurons.
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PMID:Organized ribosome-containing structural domains in axons. 1913 68

More than 150 genes have been identified that affect skin color either directly or indirectly, and we review current understanding of physiological factors that regulate skin pigmentation. We focus on melanosome biogenesis, transport and transfer, melanogenic regulators in melanocytes, and factors derived from keratinocytes, fibroblasts, endothelial cells, hormones, inflammatory cells, and nerves. Enzymatic components of melanosomes include tyrosinase, tyrosinase-related protein 1, and dopachrome tautomerase, which depend on the functions of OA1, P, MATP, ATP7A, and BLOC-1 to synthesize eumelanins and pheomelanins. The main structural component of melanosomes is Pmel17/gp100/Silv, whose sorting involves adaptor protein 1A (AP1A), AP1B, AP2, and spectrin, as well as a chaperone-like component, MART-1. During their maturation, melanosomes move from the perinuclear area toward the plasma membrane. Microtubules, dynein, kinesin, actin filaments, Rab27a, melanophilin, myosin Va, and Slp2-a are involved in melanosome transport. Foxn1 and p53 up-regulate skin pigmentation via bFGF and POMC derivatives including alpha-MSH and ACTH, respectively. Other critical factors that affect skin pigmentation include MC1R, CREB, ASP, MITF, PAX3, SOX9/10, LEF-1/TCF, PAR-2, DKK1, SCF, HGF, GM-CSF, endothelin-1, prostaglandins, leukotrienes, thromboxanes, neurotrophins, and neuropeptides. UV radiation up-regulates most factors that increase melanogenesis. Further studies will elucidate the currently unknown functions of many other pigment genes/proteins. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.
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PMID:Physiological factors that regulate skin pigmentation. 1944 48

Pigment organelles, or melanosomes, are transported by kinesin, dynein, and myosin motors. As such, melanosome transport is an excellent model system to study the functional relationship between the microtubule- and actin-based transport systems. In mammalian melanocytes, it is well known that the Rab27a/melanophilin/myosin Va complex mediates actin-based transport in vivo. However, pathways that regulate the overall directionality of melanosomes on the actin/microtubule networks have not yet been delineated. Here, we investigated the role of PKA-dependent phosphorylation on the activity of the actin-based Rab27a/melanophilin/myosin Va transport complex in vitro. We found that melanophilin, specifically its C-terminal actin-binding domain (ABD), is a target of PKA. Notably, in vitro phosphorylation of the ABD closely recapitulated the previously described in vivo phosphorylation pattern. Unexpectedly, we found that phosphorylation of the ABD affected neither the interaction of the complex with actin nor its movement along actin tracks. Surprisingly, the phosphorylation state of melanophilin was instead important for reversible association with microtubules in vitro. Dephosphorylated melanophilin preferred binding to microtubules even in the presence of actin, whereas phosphorylated melanophilin associated with actin. Indeed, when actin and microtubules were present simultaneously, melanophilin's phosphorylation state enforced track selection of the Rab27a/melanophilin/myosin Va transport complex. Collectively, our results unmasked the regulatory dominance of the melanophilin adaptor protein over its associated motor and offer an unexpected mechanism by which filaments of the cytoskeletal network compete for the moving organelles to accomplish directional transport on the cytoskeleton in vivo.
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PMID:Myosin Va's adaptor protein melanophilin enforces track selection on the microtubule and actin networks in vitro. 2855 19

Organelle positioning within neurites is required for proper neuronal function. In dendrites, with their complex cytoskeletal organization, transport of organelles is guided by local specializations of the microtubule and actin cytoskeleton, and by coordinated activity of different motor proteins. Here, we focus on the actin cytoskeleton in the dendritic shaft and describe dense structures consisting of longitudinal and branched actin filaments. These actin patches are devoid of microtubules and are frequently located at the base of spines, or form an actin mesh around excitatory shaft synapses. Using lysosomes as an example, we demonstrate that the presence of actin patches has a strong impact on dendritic organelle transport, as lysosomes frequently stall at these locations. We provide mechanistic insights on this pausing behavior, demonstrating that actin patches form a physical barrier for kinesin-driven cargo. In addition, we identify myosin Va as an active tether which mediates long-term stalling. This correlation between the presence of actin meshes and halting of organelles could be a generalized principle by which synapses control organelle trafficking.
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PMID:F-actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes. 3126 65


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