Cargo transport: molecular motors navigate a complex cytoskeleton

Ross, Jennifer L.; Ali, M. Yusuf; Warshaw, David M.

doi:10.1016/j.ceb.2007.11.006

Cited by 304 publications

(277 citation statements)

References 43 publications

(22 reference statements)

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“…On the other hand, another study found that kinesin had a higher probability of detachment when encountering tau patches on the MT [97]. 60 As a consequence of the fact that tau proteins may prevent locally kinesins to bind, tau proteins have been also shown to favor switches of cargos from one microtubule to another one [310], a feature which may be helpful in crowded environments.…”

Section: Modification Of Mts By Maps : the Example Of Tau Proteinsmentioning

confidence: 99%

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

2015

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Cells are the elementary units of living organisms, which are able to carry out many vital functions. These functions rely on active processes on a microscopic scale. Therefore, they are strongly out-of-equilibrium systems, which are driven by continuous energy supply. The tasks that have to be performed in order to maintain the cell alive require transportation of various ingredients, some being small, others being large. Intracellular transport processes are able to induce concentration gradients and to carry objects to specific targets. These processes cannot be carried out only by diffusion, as cells may be crowded, and quite elongated on molecular scales. Therefore active transport has to be organized.The cytoskeleton, which is composed of three types of filaments (microtubules, actin and intermediate filaments), determines the shape of the cell, and plays a role in cell motion. It also serves as a road network for a special kind of vehicles, namely the cytoskeletal motors. These molecules can attach to a cytoskeletal filament, perform directed motion, possibly carrying along some cargo, and then detach.It is a central issue to understand how intracellular transport driven by molecular motors is regulated. The interest for this type of question was enhanced when it was discovered that intracellular transport breakdown is one of the signatures of some neuronal diseases like the Alzheimer.We give a survey of the current knowledge on microtubule based intracellular transport. Our review includes on the one hand an overview of biological facts, obtained from experiments, and on the other hand a presentation of some modeling attempts based on cellular automata. We present some background knowledge on the original and variants of the TASEP (Totally Asymmetric Simple Exclusion Process), before turning to more application oriented models. After addressing microtubule based transport in general, with a focus on in vitro experiments, and on cooperative effects in the transportation of large cargos by multiple motors, we concentrate on axonal transport, because of its relevance for neuronal diseases. Some important characteristics of axonal transport is that it takes place in a confined environment; Besides several types of motors are involved, that move in opposite directions. It is a challenge to understand how this bidirectional transport is organized. We review several features that could contribute to the efficiency of bidirectional transport in the axon, including in particular the role of motor-motor interactions and of the dynamics of the underlying microtubule network. Finally, we also discuss some open questions that may be relevant for future research in this field.

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Section: Modification Of Mts By Maps : the Example Of Tau Proteinsmentioning

confidence: 99%

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

2015

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“…Myosin is composed of two myosin heavy chains, two regulatory light chains, and two essential light chains (35). As a major form of cytoskeleton-dependent intracellular transport, myosin is known to bind actin filaments and to function in the transport of protein cargos in the cytoplasm (36,37). Interactions between SPATA6 and myosin light and heavy chain subunits strongly suggest that SPATA6 is involved in myosin-based microfilament transport, which may be responsible for transporting basic building blocks for the assembly of the segmented columns during connecting piece formation in developing spermatids (Fig.…”

Section: Significancementioning

confidence: 99%

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Yuan

Stratton

Bao

et al. 2015

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

129

116

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"Pinhead sperm," or "acephalic sperm," a type of human teratozoospermia, refers to the condition in which ejaculate contains mostly sperm flagella without heads. Family clustering and homogeneity of this syndrome suggests a genetic basis, but the causative genes remain largely unknown. Here we report that Spata6, an evolutionarily conserved testis-specific gene, encodes a protein required for formation of the segmented columns and the capitulum, two major structures of the sperm connecting piece essential for linking the developing flagellum to the head during late spermiogenesis. Inactivation of Spata6 in mice leads to acephalic spermatozoa and male sterility. Our proteomic analyses reveal that SPATA6 is involved in myosin-based microfilament transport through interaction with myosin subunits (e.g., MYL6).M ale gametes-spermatozoa-are produced in the testis through a process termed spermatogenesis, which can be divided into three phases: mitotic, meiotic, and haploid (1). In the mitotic phase, spermatogonial stem cells proliferate and differentiate into spermatogonia, which subsequently enter the meiotic phase and become spermatocytes. Spermatocytes undergo crossover, followed by two consecutive meiotic cell divisions to produce haploid spermatids. Spermatids then undergo a multistep differentiation process, also called spermiogenesis, to form spermatozoa. Severe disruptions in either the mitotic or the meiotic phase tend to cause azoospermia, whereas spermiogenic defects often lead to reduced sperm counts, aberrant sperm motility, and deformed spermatozoa, a condition termed oligoasthenoteratozoospermia (OAT) in humans (2, 3).OAT accounts for a significant proportion of male idiopathic infertility cases (2, 4). Numerous cases of acephalic spermatozoa have been reported in teratozoospermic patients (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In these patients, the major anomaly lies in headless spermatozoa in the ejaculate, and the headless spermatozoa were initially called "pinhead sperm" because the investigators mistakenly regarded the retained cytoplasmic droplets, which are usually attached to the midprincipal piece junction of the flagella, as the heads of reduced size (8,13,14). Extensive ultrastructral studies on humans and animals with acephalic spermatozoa suggest that this condition results from defects in formation of the connecting piece of spermatozoa during late spermiogenesis, including failure for the proximal centrioles to attach normally to the caudal portion of the sperm nuclei, leading to abnormal head-midpiece alignment, or a nuclear defect that interferes with formation of the implantation fossa, the normal lodging site for the sperm proximal centriole (16). Aberrant formation of the connecting piece leads to independent development of the sperm heads and flagella, and eventually these structures become separated within the seminiferous tubules or during their transition through the seminal tract as a consequence of increased instability of the head-midpiece junction (16,18)....

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“…The linker of choice was (GSG) 2 as it has been previously used on anchoring domains on myosin VI (21). The introduction of flexibility into the system is motivated by myosin V, which contains a free swiveling joint between the two lever arms and before the coiled-coil domain, allowing for a spherical search for the most favorable binding site (1,22). These swivel mutants will disrupt any structurally rigid elements in myosin X and, if our model is valid, result in a motor domain that is allowed to freely search for the next binding site.…”

Section: Structural Properties Of the Tail Region Impart Fascin Bundlementioning

confidence: 99%

“…The essential role of cytoskeletal motor proteins in organizing cellular compartments and cargoes is widely accepted (1). However, many of the molecular details of the overall transport and organization process are poorly understood.…”

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confidence: 99%

Structured Post-IQ Domain Governs Selectivity of Myosin X for Fascin-Actin Bundles

Nagy

Rock

2010

Journal of Biological Chemistry

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Without guidance cues, cytoskeletal motors would traffic components to the wrong destination with disastrous consequences for the cell. Recently, we identified a motor protein, myosin X, that identifies bundled actin filaments for transport. These bundles direct myosin X to a unique destination, the tips of cellular filopodia. Because the structural and kinetic features that drive bundle selection are unknown, we employed a domain-swapping approach with the nonselective myosin V to identify the selectivity module of myosin X. We found a surprising role of the myosin X tail region (post-IQ) in supporting long runs on bundles. Moreover, the myosin X head is adapted for initiating processive runs on bundles. We found that the tail is structured and biases the orientation of the two myosin X heads because a targeted insertion that introduces flexibility in the tail abolishes selectivity. Together, these results suggest how myosin motors may manage to read cellular addresses.The essential role of cytoskeletal motor proteins in organizing cellular compartments and cargoes is widely accepted (1). However, many of the molecular details of the overall transport and organization process are poorly understood. These essential features include how motors engage cargoes at their source, how motors are activated once they engage cargo, how they choose the correct set of cytoskeletal tracks, how they disengage from cargo at their destination, and how they return to sources of cargo. Clearly, errors at any of these stages would lead to faults in cellular organization and misplaced cargoes.To begin to address these questions we have focused on a particular motor protein, myosin X, due to its ability to navigate to a precise location within the cell (2). Myosin X is found at the mitotic and meiotic spindle, where it sets the orientation of the spindle relative to the substrate and influences spindle length (3, 4). However, myosin X is more commonly found in interphase cells at the tips of filopodia (5). These long, slender projections at the leading edge of migrating cells are involved in cell motility and environmental sensing. Myosin X transports components such as Ena/VASP and integrins that are found in the filopodial tip complex (2, 6). The early work by Berg et al. (5) demonstrated that myosin X reaches filopodial tips under its own power. Recently, we found that myosin X identifies filopodia by recognizing the fascin-bundled actin filaments found in the filopodial core (7). Myosin X takes long processive runs along these tightly bundled actin filaments while largely ignoring isolated actin filaments found throughout the cell. In contrast, myosin V does not distinguish between single actin filaments and bundled actin filaments when taking processive runs.Here, we seek to identify the "selectivity module" that allows myosin X to recognize bundled actin filaments. Our first approach is to swap similar domains between the selective myosin X and the nonselective myosin V. In this approach, we are aided by the fact that both m...

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Cargo transport: molecular motors navigate a complex cytoskeleton

Cited by 304 publications

References 43 publications

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Structured Post-IQ Domain Governs Selectivity of Myosin X for Fascin-Actin Bundles

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