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Samara Reck-Peterson

Research

The contents of eukaryotic cells are highly dynamic, yet organized spatially and temporally. This is achieved primarily by the microtubule cytoskeleton and associated transport machinery, whose fundamental nature is highlighted by the many neurological diseases caused by mutations in them. The overarching goal of the Reck-Peterson lab is to understand how this system works at the molecular, cellular, and organismal scales.

The Reck-Peterson lab is highly interdisciplinary and we use in vitro biochemical reconstitution, protein engineering, single-molecule imaging, proteomics, live-cell imaging, and genetics to achieve our goals. Through collaborative projects with others at UC San Diego we use cryo-electron microscopy (with Andres Leschziner’s lab) and cryo-electron tomography (with Elizabeth Villa’s lab) to incorporate a structure-guided approach to understanding intracellular transport, and we develop testable quantitative physical models of transport (with Elena Koslover’s lab).

The Reck-Peterson lab has made major contributions to determining how the dynein motor works and is regulated, to developing tools and screening strategies to study bi-directional movement of cargos on microtubules, to understanding the regulation of intracellular transport in cells, and most recently to determining how defects in microtubule-based trafficking may impact Parkinson’s Disease.

Major projects in the lab include:

(1) How does the dynein motor work?

Dynein is a large and complicated molecular machine. We have made contributions to developing recombinant systems to express dynein, determining how dynein steps along microtubules, and determining how it is regulated by Lis1. Both the dynein motor encoding gene ( DYNC1H1) and the LIS1 gene are mutated in the neurodevelopmental disease lissencephaly. We have shown that the Lis1 protein binds directly to dynein’s motor domain and impacts its mechanochemical cycle (dynein is a AAA ATPase and its nucleotide cycle controls its interactions with its microtubule track). We also discovered that Lis1 promotes the formation of activated dynein complexes. Activated dynein complexes include 12 dynein subunits, 23 dynactin subunits and a dimeric “activating adaptor”.

Current efforts in the lab are focused on determining how Lis1 promotes the formation of these massive activated dynein complexes.

(2) How is cargo-specificity achieved?

In mammals, the dynein motor transports dozens if not hundreds of distinct cargos. How does it do this with specificity? Our past work used two complementary discovery-based approaches—genetics and proteomics—to identify molecules responsible for specifying dynein’s many functions. One mechanism revealed by our past work was organelle hitchhiking, where cargos link to motors indirectly, by attaching themselves to other cargos that are directly bound to the motors. A second strategy for achieving cargo specificity is the expansion of dynein activating adaptor genes in vertebrates. However, the molecular connections between most activating adaptors and dynein’s cargo are unknown.

A current goal is to determine the mechanisms underlying hitchhiking and the linkages between different activating adaptors and their cargos.

(3) Why do perturbations to the transport machinery cause disease?

Mutations in many components of the transport machinery (the motors, the tracks and regulators of both) are directly linked to a wide variety of neurodevelopmental and neurodegenerative diseases. In addition to our studies on Lis1, we recently began working on LRRK2. The LRRK2 gene is one of the most commonly mutated genes in familial Parkinson’s disease. In collaboration with the Leschziner lab, we showed that LRRK2 binds directly to microtubules in the absence of any other proteins. By doing so it can act as a “roadblock” for dynein and kinesin microtubule-based motors, nearly completely abolishing their movement at low nanomolar concentrations.

Current efforts are focused on determining how LRRK2 binds to microtubules and how pathogenic LRRK2 leads to defects in microtubule-based transport.

(4) Other new directions:

We are also exploring a number of new directions related to transport in a variety of organisms using a wide range of techniques and methods.

Select Publications

  • Deniston CK*, Salogiannis J*, Mathea S*, Snead DM, Lahiri I, Matyszewski M, Donosa O, Watanabe R, Bohning J, Shiau AK, Knapp S, Villa E, Reck-Peterson SL‡, Leschziner AL‡. (2020) Parkinson’s Disease-linked LRRK2 structure and model for microtubule interaction. Nature 588: 344-349.
    • Hot Topics: Olszewska and Lang (2020). “Opening” new insights into LRRK2 conformation and the microtubule”. Movement Disorders 35: 2162-2163.
  • Htet ZM*, Gillies JP*, Baker RW, Leschziner AL, DeSantis ME‡, Reck-Peterson SL‡. (2020) Lis1 promotes the formation of maximally activated cytoplasmic dynein-1 complexes. Nature Cell Biology 5: 518-525.
    • News and Views: McKenney RJ (2020). Lis1 cracks open dynein. Nat Cell Biol. 22: 515-517.
  • Reck-Peterson SL‡, Redwine WB, Vale RD, Carter AP‡. (2018) The cytoplasmic dynein transport machinery and its many cargoes. Nat Rev Mol Cell Biol. doi: 10.1038/s41580-018-0004-3.
  • DeSantis ME*, Cianfrocco MA*, Htet ZM*, Tran PT, Reck-Peterson SL‡, Leschziner AE‡. (2017) Lis1 has two opposing modes of regulating cytoplasmic dynein. Cell 170: 1197-1208. PMC5625841
  • Redwine WB*, DeSantis ME*, Hollyer I, Htet ZM, Tran PT, Swanson SK, Florens L, Washburn MP, Reck-Peterson SL. (2017) The human cytoplasmic dynein interactome reveals novel activators of motility. eLife 6:e28257.
  • Salogiannis J, Egan MJ, Reck-Peterson SL. (2016) Peroxisomes move by hitchhiking on early endosomes using the novel linker protein PxdA. J Cell Biol 212: 289-296.
    • In this issue: Short B. (2016) PxdA helps peroxisomes hitch a ride. J Cell Biol 212: 258.
    • Research highlight: Strzyz P. (2016) How peroxisomes hitchhike on endosomes. Nature Reviews Mol Cell Biol. 17: 134.
  • Derr ND*, Goodman BS*, Jungmann R, Leschziner AE, Shih WM, Reck-Peterson SL. (2012) Tug of-war in motor protein ensembles revealed with a programmable DNA origami scaffold. Science 338: 662-665.
    • Perspective: Diehl MR. (2012). Templating a Molecular Tug-of-War. Science 338: 626-627.
  • Huang J*, Roberts A*, Leschziner L, Reck-Peterson SL. (2012) Lis1 acts as a "clutch" between the ATPase and microtubule-binding domains of the dynein motor. Cell 150: 975-986.
    • Preview: Trokter M and Surrey T. (2012) LIS1 Clamps Dynein to the Microtubule. Cell 150: 877- 879.

All Reck-Peterson Lab publications: https://pubmed.ncbi.nlm.nih.gov/?term=Reck-Peterson+S%5BAuthor%5D&sort=date

*co-first author
‡co-corresonding author

Biography

Samara Reck-Peterson received her Ph.D. from the Department of Cell Biology at Yale University and did postdoctoral research with Ron Vale at the University of California, San Francisco. She was an Assistant and Associate professor of Cell Biology at Harvard Medical School and the Associate Director of the Biological and Biomedical Sciences Graduate Program at Harvard Medical School. She was recruited to UC San Diego in 2015. Dr. Reck-Peterson was the recipient of an NIH New Innovator Award, was named a Howard Hughes Medical Institute-Simons Faculty Scholar, and is currently an Investigator of the Howard Hughes Medical Institute. She is also the Faculty Director of the Nikon Imaging Center at UC San Diego.