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Samara Reck-Peterson

Research

Eukaryotic cells use microtubule tracks to move cargo over long distances. There are two types of molecular motors that move on microtubules: dyneins and kinesins. Dyneins move cargo towards the minus ends of microtubules, typically towards the cell interior. Kinesins move cargo in the opposite direction, generally towards the cell surface. Our lab is tackling three broad questions.

  • How does the dynein motor work and how is it regulated?
  • What are the rules governing transport in cells?
  • Why do defects in transport cause disease?

How does the dynein motor work and how is it regulated?

Cytoplasmic dynein-1 is the only motor used for long-distance minus-end-directed microtubule-based trafficking in eukaryotic cells ranging from human neurons to the hyphae of filamentous fungi. Yet, it transports dozens, if not hundreds of different cargos. One of our lab’s goals is to understand how this large, multi-subunit, motor is regulated. Dynein has two regulators that are conserved and required for most (perhaps all) of its functions: the dynactin complex and Lis1/ Nudel. Current experiments in the lab are focused on determining how these regulators work. We use quantitative approaches to do this, including single-molecule imaging, cryo-electron microscopy (in collaboration with the lab of Andres Leschziner), proteomics, and live-cell imaging.

What are the rules governing transport?

In addition to cytoplasmic dynein-1, at least 15 kinesin motors (in humans) are responsible for moving cargo in the opposite direction as dynein. This small subset of motors is responsible for nearly all long distance transport in eukaryotic cells. What is the full list of dynein and kinesin cargos? What links the motors to different cargos? How is specificity achieved? Do all cargos have a distinct mechanism for recruiting motors? We are addressing these questions using two different discovery-based approaches:

  1. We use the filamentous fungus, Aspergillus nidulans, as a powerful genetic system to dissect microtubule-based transport. We have conducted screens to identify genes required for the transport of endosomes, peroxisomes, and nuclei. Current projects in the lab are characterizing these novel transport factors.
  2. We also use proteomic approaches to identify the dynein and kinesin “transportome”. Current efforts in the lab are focused on using proximity-dependent labeling in living human cells to identify the dynein proteome.

Why do defects in transport cause disease?

Mutations in every component of the transport system—tubulins (the building blocks of microtubules), dynein, kinesins, and proteins that regulate the motors or their tracks—cause neurological diseases. For example, mutations in cytoplasmic dynein-1 cause a peripheral neuropathy called Charcot Marie Tooth type 2, Spinal Muscular Atrophy (SMA), malformation of cortical development, and intellectual disability. Like some mutations in dynein, mutations in the dynein activator BICD2 also cause SMA. Mutations in a subunit of dynactin result in motor neuron disease and Perry syndrome, an early onset form of Parkinson’s disease. Defects in microtubule-based axonal transport are also observed in other neurodegenerative diseases including Amyotrophic Lateral Sclerosis, Alzheimer’s and Huntington’s, suggesting that there may be additional links between dynein and neurological disease yet to be uncovered. One hypothesis is that neurodegenerative diseases can result from the compromised trafficking of particular cargos. Current projects in the lab are aimed at identifying which cargos or points of regulation are defective in disease states.

Publications

  • Salogiannis J, Egan MJ, Reck-Peterson SL. (2016) Peroxisomes move by hitchhiking on early endosomes using the novel linker proteins PxdA. J Cell Biol 212: 289-296.
    Commentaries on this research appeared in: J Cell Biol 212: 258 and Nat Rev Mol Cell Biol 17: 134.
  • Cianfrocco MA, DeSantis ME, Leschziner AE, Reck-Peterson SL. (2015) Mechanism and Regulation of Cytoplasmic Dynein. Annu Rev Cell Dev Biol 31: 83-108.
  • Toropova K*, Zou S*, Roberts AJ, Redwine WB, Goodman BS, Reck-Peterson SL#, Leschziner AE#. (2014). Lis1 regulates dynein by sterically blocking its mechanochemical cycle. eLIFE 3:e03372.
  • Roberts AJ, Goodman BS, Reck-Peterson SL. (2014) Reconstitution of dynein transport to the microtubule plus end by kinesin. eLIFE 3:e02641.
  • Tan K, Roberts AJ, Chonofsky M, Egan MJ, Reck-Peterson SL. (2014) A microscopy-based screen employing multiplex genome sequencing identifies cargo-specific requirements for dynein velocity. Mol Biol Cell 25: 669-678.
  • 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 origmai scaffold. Science 338: 662-665.
  • Redwine WB*, Hernandez-Lopez R*, Zou S, Huang J, Reck-Peterson SL, Leschziner AE. (2012) Structural basis for microtubule binding and release by dynein. Science 337: 1532-1536.
  • Huang J*, Roberts AJ*, Leschziner AE, Reck-Peterson SL. (2012) Lis1 acts as a "clutch" between the ATPase and microtubule-binding domains of the dynein motor. Cell 150: 975-986.
    Commentary on this research appeared in: Cell 150: 877-879
  • Egan M, Tan K, Reck-Peterson SL. (2012) Lis1 is an initiation factor for dynein-driven organelle transport. J Cell Biol 197: 971-982.
    Commentary on this research appeared in: J Cell Biol 197: 852.
  • Laan L, Pavin N, Husson J, Romet-Lemonne G, van Duin M, Lopez MP, Vale RD, Julicher F, Reck-Peterson SL, Dogterom M. (2012) “Cortical” dynein controls microtubule dynamics and length, generating pulling forces that reliably position microtubule asters. Cell 148: 502-514.
  • Qiu W*, Derr ND*, Goodman BS, Villa E, Wu D, Shih W, Reck-Peterson SL. (2012) Dynein achieves processive motion using both stochastic and coordinated stepping. Nat Struct Mol Biol 19: 193-200.
    Commentary on this research appeared in: Nature 482: 7383.
  • Kardon J, Reck-Peterson SL, Vale RD. (2009) Regulation of the processivity and intracellular localization of S. cerevisiae dynein by dynactin. PNAS 106: 5669-74.
  • Cho C, Reck-Peterson SL, Vale RD. (2008) Cytoplasmic dynein's regulatory ATPase sites affect processivity and force generation. J Biol Chem 283: 25839-45.
  • Gennerich A, Carter AP, Reck-Peterson SL, Vale RD. (2007) Force-induced bidirectional stepping of cytoplasmic dynein. Cell 131: 952-965.
  • Reck-Peterson SL, Yildiz Y*, Carter AP*, Gennerich A, Zhang N, and Vale RD. (2006) Single molecule analysis of dynein processivity and stepping behavior.Cell 126: 335-348.
    Commentaries on this research appeared in: Cell 126: 242-244, Nat Rev Mol Cell Biol 7: 625, J Cell Biol 172: 486-492.

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 joined the UCSD faculty in 2015. Dr. Reck-Peterson was the recipient of an NIH New Innovator Award.