Richard B. Vallee

Columbia University

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Howard S. Shpetner

University of Massachusetts Chan Medical School

Kevin T. Vaughan

University of Notre Dame

Bryce M. Paschal

University of Virginia

Richard J. McKenney

University of California, Davis

Tiago J. Dantas

Universidade do Porto

Denis Dujardin

Laboratoire de Biophotonique et Pharmacologie

Steven P. Gross

University of California, Irvine

Julie Yi

Columbia University Irving Medical Center

Peter Höök

University of Florida

Erika L.F. Holzbaur

University of Pennsylvania

Cooperative Institutions

Columbia University

University of Massachusetts Chan Medical School

University College London

Centre National de la Recherche Scientifique

Columbia University Irving Medical Center

Harvard University

Howard Hughes Medical Institute

National Institutes of Health

University of California, Los Angeles

University of Virginia

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Roles of the multivalent dynein adaptors BicD2 and RILP in neurons

Neuroscience Letters (2021)

Richard B. Vallee Julie Yi Sebastián Quintremil Noopur V. Khobrekar

10.1016/j.neulet.2021.135796

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Citations (3)

KIF1A inhibition immortalizes brain stem cells but blocks BDNF-mediated neuronal migration

Nature Neuroscience (2016)

Aurélie Carabalona Daniel Jun-Kit Hu Richard B. Vallee

Ectopic expression

10.1038/nn.4213

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Citations (54)

Synthesis and Biological Evaluation of Purealin and Analogues as Cytoplasmic Dynein Heavy Chain Inhibitors

Journal of Medicinal Chemistry (2006)

Guangyu Zhu Fanglong Yang Raghavan Balachandran Peter Höök Richard B. Vallee

Cytoplasmic dynein plays important roles in membrane transport, mitosis, and other cellular processes. A few small-molecule inhibitors of cytoplasmic dynein have been identified. We report here the first synthesis of purealin, a natural product isolated from the sea sponge Psammaplysilla purea, which is known to inhibit axonemal dynein. Also described are the first syntheses, by modular amide coupling reactions, of the natural product purealidin A (a component of purealin) and a small library of analogues. The library was examined for inhibition of cytoplasmic dynein heavy chain and cell growth. The compounds showed effective antiproliferative activity against a mouse leukemia cell line but selective activities against human carcinoma cell lines. Purealin and some of the analogues inhibited the microtubule-stimulated ATPase activity of recombinant cytoplasmic dynein heavy chain motor domain. The inhibitory effect of purealin was concentration dependent and uncompetitive, supporting the hypothesis that it does not compete with the binding of ATP.

Dynactin

Dynein ATPase

Natural product

10.1021/jm051030l

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Citations (45)

The role of dynein and other microtubule-activated ATPases in mitosis.

PubMed (1989)

Richard B. Vallee Howard S. Shpetner Bryce M. Paschal

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Citations (3)

Cytoplasmic dynein and its regulators in neocortical development and disease

Elsevier eBooks (2017)

David J. Doobin Richard B. Vallee

Neocortex

Dynactin

Microcephaly

10.1016/b978-0-12-809470-9.00012-6

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Citations (1)

Cytoplasmic dynein: advances in microtubule-based motility

Trends in Cell Biology (1991)

Richard B. Vallee

Dynactin

Organelle

Kinesin

Dynein ATPase

10.1016/0962-8924(91)90066-i

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Citations (33)

Microtubule-associated proteins 1A and LC2. Two proteins encoded in one messenger RNA.

Journal of Biological Chemistry (1992)

Anja Langkopf James A. Hammarback Rachel Müller Richard B. Vallee Craig C. Garner

The deduced amino acid sequence for the filamentous microtubule-associated protein (MAP) 1A, thought to be involved in stabilizing the mature neuronal cytoskeleton, has been determined from a series of overlapping cDNA clones. Though previously described as biochemically and immunologically distinct from MAP1B, we now demonstrate that MAP1A is structurally related to MAP1B, a protein associated with neurite outgrowth and process plasticity. The two MAPs exhibit regional amino acid sequence similarities spanning their potential microtubule binding domains placing both into a new MAP family. The cDNA sequence encoding MAP1A was also found to encode one of its associated light chains (LC) called LC2. Both proteins are found on a single mRNA in the same open reading frame and are translated as a pre-MAP1A/LC2-protein. The topological relationship between MAP1A and LC2 coding sequences is, therefore, identical to that previously shown for MAP1B and LC1 (Hammarback, J. A., Obar, R. A., Hughes, S. M., and Vallee, R. B. (1991) Neuron 7, 129-139). Based on these and earlier results, we conclude that LC1 and LC2 are structurally related polypeptides generated from distinct MAP polyprotein precursors but free to exchange between the two MAPs.

Five-prime cap

10.1016/s0021-9258(18)42039-x

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Citations (113)

Conformational Changes in the Adenovirus Hexon Subunit Responsible for Regulating Cytoplasmic Dynein Recruitment

Journal of Virology (2014)

Julian Scherer Richard B. Vallee

ABSTRACT Virus capsids provide genome protection from environmental challenges but are also poised to execute a program of compositional and conformational changes to facilitate virion entry and infection. The most abundant adenovirus serotype 5 (AdV5) capsid protein, hexon, directly recruits the motor protein cytoplasmic dynein following virion entry. Dynein recruitment is crucial for capsid transport to the nucleus and requires the transient exposure of AdV5 hexon to low pH, presumably mimicking passage through the endosomal compartment. These results suggest a pH-dependent capsid modification during early infection. The changes to hexon structure controlling this behavior have not been explored. We report that hexon remains trimeric at low pH but undergoes more subtle conformational changes. These changes are indicated by increased sensitivities to SDS-mediated dissociation and dispase proteolysis. Both effects are reversed at neutral pH, as is dynein binding by low-pH-treated hexon. Dispase cleavage, which we find maps to a specific site within hypervariable region 1 (HVR1) of AdV5 hexon, has no apparent effect on virion entry but completely inhibits its transport to the nucleus. In addition, an AdV5 mutant containing HVR1 of AdV48 is unable to bind dynein and is strongly inhibited in the postentry transport step. These results reveal that conformational changes involving hexon HVR1 are the basis for a novel viral mechanism controlling capsid transport to the nucleus. IMPORTANCE The adenovirus serotype 5 (AdV5) capsid protein hexon recruits the molecular motor protein cytoplasmic dynein in a pH-dependent manner, a function critical for efficient transport toward the nucleus and AdV5 infectivity. In this work, we describe how low-pH exposure induces reversible structural changes in AdV5 hexon and how these changes affect dynein binding. In addition, we identified a pH-sensitive dispase cleavage site in hexon HVR1, which depends on the same structural changes and furthermore regulates dynein recruitment and capsid redistribution in infected cells. These data provide the first evidence relating long-known but subtle pH-dependent structural changes in hexon to a more recently established essential but poorly understood role in virus transport. These results have broad implications for understanding virus infectivity in general, and our ability to block the recruitment mechanism has potential therapeutic implications as well.

Dynactin

10.1128/jvi.02889-14

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Citations (23)

Two decades of cytoplasmic dynein: From fast to forceful

Richard J. McKenney Richard B. Vallee

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Recruitment of dynein to late endosomes and lysosomes through light intermediate chains

Molecular Biology of the Cell (2010)

Serena Tan Julian Scherer Richard B. Vallee

Cytoplasmic dynein is involved in a wide range of cellular processes, but how it is regulated and how it recognizes an extremely wide range of cargo are incompletely understood. The dynein light intermediate chains, LIC1 and LIC2 (DYNC1LI1 and DYNC1LI2, respectively), have been implicated in cargo binding, but their full range of functions is unknown. Using LIC isoform-specific antibodies, we report the first characterization of their subcellular distribution and identify a specific association with elements of the late endocytic pathway, but not other vesicular compartments. LIC1 and LIC2 RNA interference (RNAi) each specifically disrupts the distribution of lysosomes and late endosomes. Stimulation of dynein-mediated late-endosomal transport by the Rab7-interacting lysosomal protein (RILP) is reversed by LIC1 RNAi, which displaces dynein, but not dynactin, from these structures. Conversely, expression of ΔN-RILP or the dynactin subunit dynamitin each fails to displace dynein, but not dynactin. Thus, using a variety of complementary approaches, our results indicate a novel specific role for the LICs in dynein recruitment to components of the late endocytic pathway.

Dynactin

Dynein ATPase

10.1091/mbc.e10-02-0129

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Citations (87)