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Autoregulatory mechanism for dynactin control of processive and diffusive dynein transport.

ABSTRACT: Dynactin is the longest known cytoplasmic dynein regulator, with roles in dynein recruitment to subcellular cargo and in stimulating processive dynein movement. The latter function was thought to involve the N-terminal microtubule-binding region of the major dynactin polypeptide p150(Glued), although recent results disputed this. To understand how dynactin regulates dynein we generated recombinant fragments of the N-terminal half of p150(Glued). We find that the dynein-binding coiled-coil ?-helical domain CC1B is sufficient to stimulate dynein processivity, which it accomplishes by increasing average dynein step size and forward-step frequency, while decreasing lateral stepping and microtubule detachment. In contrast, the immediate upstream coiled-coil domain, CC1A, activates a surprising diffusive dynein state. CC1A interacts physically with CC1B and interferes with its effect on dynein processivity. We also identify a role for the N-terminal portion of p150(Glued) in coordinating these activities. Our results reveal an unexpected form of long-range allosteric control of dynein motor function by internal p150(Glued) sequences, and evidence for p150(Glued) autoregulation.

SUBMITTER: Tripathy SK

PROVIDER: S-EPMC4250405 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Autoregulatory mechanism for dynactin control of processive and diffusive dynein transport.

Tripathy Suvranta K SK Weil Sarah J SJ Chen Chen C Anand Preetha P Vallee Richard B RB Gross Steven P SP

Nature cell biology 20141124 12

Dynactin is the longest known cytoplasmic dynein regulator, with roles in dynein recruitment to subcellular cargo and in stimulating processive dynein movement. The latter function was thought to involve the N-terminal microtubule-binding region of the major dynactin polypeptide p150(Glued), although recent results disputed this. To understand how dynactin regulates dynein we generated recombinant fragments of the N-terminal half of p150(Glued). We find that the dynein-binding coiled-coil α-heli ...[more]

PMID: 25419851

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Project description:Human immunodeficiency virus type 1 (HIV-1) infection depends on efficient intracytoplasmic transport of the incoming viral core to the target cell nucleus. Evidence suggests that this movement is facilitated by the microtubule motor dynein, a large multiprotein complex that interacts with dynactin and cargo-specific adaptor proteins for retrograde movement via microtubules. Dynein adaptor proteins are necessary for activating dynein movement and for linking specific cargoes to dynein. We hypothesized that HIV-1 engages the dynein motor complex via an adaptor for intracellular transport. Here, we show that small interfering RNA depletion of the dynein heavy chain, components of the dynactin complex, and the dynein adaptor BICD2 reduced cell permissiveness to HIV-1 infection. Cell depletion of dynein heavy chain and BICD2 resulted in impaired HIV-1 DNA accumulation in the nucleus and decreased retrograde movement of the virus. Biochemical studies revealed that dynein components and BICD2 associate with capsid-like assemblies of the HIV-1 CA protein in cell extracts and that purified recombinant BICD2 binds to CA assemblies in vitro Association of dynein with CA assemblies was reduced upon immunodepletion of BICD2 from cell extracts. We conclude that BICD2 is a capsid-associated dynein adaptor utilized by HIV-1 for transport to the nucleus.IMPORTANCE During HIV-1 infection, the virus must travel across the cytoplasm to enter the nucleus. The host cell motor protein complex dynein has been implicated in HIV-1 intracellular transport. We show that expression of the dynein heavy chain, components of the dynein-associated dynactin complex, and the dynein adaptor BICD2 in target cells are important for HIV-1 infection and nuclear entry. BICD2 interacts with the HIV-1 capsid in vitro, suggesting that it functions as a capsid-specific adaptor for HIV-1 intracellular transport. Our work identifies specific host proteins involved in microtubule-dependent HIV-1 intracellular transport and highlights the BICD2-capsid interaction as a potential target for antiviral therapy.

Dataset Information

Autoregulatory mechanism for dynactin control of processive and diffusive dynein transport.

Publications

Autoregulatory mechanism for dynactin control of processive and diffusive dynein transport.

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