The Reck-Peterson lab investigates mechanisms of intracellular transport in health and disease spanning molecular, cellular and organismal scales. Our current projects can be grouped into five major areas: 1) the function and mechanism of dynein and kinesin microtubule motors, 2) the molecular basis of Parkinson’s Disease, a disease linked to defects in intracellular transport, 3) organelle contacts and organelle hitchhiking, 4) the cell biology of secondary metabolism in filamentous fungi, and 5) the functional consequences of RNA recoding of molecular machines.

We are always opening to exploring new directions related to mechanisms of intracellular transport and welcome creative graduate students, postdoctoral fellows, and staff scientists to join us to pursue ideas they bring to the lab.

Dynein and kinesin microtubule motors

Microtubules and the dynein and kinesin motors that move along them are a complex system responsible for performing most intracellular transport of compartments that are too large to be distributed on biologically relevant timescales by diffusion. A major focus of our research has been the molecular motor cytoplasmic dynein-1 (“dynein”). When we began studying dynein, it was poorly understood compared to the other cytoskeletal motors, kinesin and myosin, largely due to its size and complexity. Our lab has played a central role in changing this. We determined how dynein steps and interacts with microtubules, how it engages with the opposite-polarity kinesin motors, and most recently how dynein autoinhibition is relieved by the Lis1 protein.

Current projects in the lab are exploring the roles of dynein and kinesin in cancer and neurodegenerative disease. We are experts in in vitro reconstitution and single-molecule and live-cell imaging and collaborate with the Leschziner lab for structural studies.

Mechanism of Leucine Rich Repeat Kinases (LRRK1 and LRRK2) and the molecular basis of LRRK2-driven Parkinson’s Disease

Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most mutated genes in familial Parkinson’s Disease (PD). Increased LRRK2 kinase activity is seen in both familial and idiopathic PD, making LRRK2 the main actionable target for PD therapeutics today, with kinase inhibitors in clinical trials. Our interest in LRRK2 is twofold: first, LRRK2 is a Rab kinase, the same family of GTPases that recruit dynein and kinesin to their membranous cargos. Second, when expressed at high concentrations LRRK2 oligomerizes on microtubules, an interaction that is enhanced by most PD mutations and LRRK2 Type-1 kinase inhibitors (the type in clinical trials). We reconstituted LRRK2 microtubule binding in vitro with pure components, solved a high-resolution structure of LRRK2 bound to microtubules with the Leschziner lab, and showed that microtubule-associated LRRK2 is a potent inhibitor of both dynein and kinesin motility at low nanomolar concentrations. Our more recent work has focused on developing tools to study LRRK2. With the Knapp lab we developed the first Type-2 kinase inhibitor that has high specificity for LRRK proteins and reported Designed Ankryin Repeat Proteins (DARPins) that bind with high affinity to LRRK2. Our work has important implications for the development of PD therapeutics and understanding possible side effects of treatment with LRRK2-specific Type-1 kinase inhibitors.   

Current projects in the lab are aimed at developing novel therapeutics for PD and determining the structure and function of both LRRK1 and LRRK2 in collaboration with the Leschziner group at WCM.

Organelle contacts and organelle hitchhiking

To complement our in vitro studies on intracellular transport, we use Aspergillus nidulans as a genetic model for long-distance microtubule transport. Our first genetic screen in A. nidulans led to the discovery of a novel type of intracellular transport that we termed “organelle hitchhiking”, where one organellar cargo moves only by attaching to another motile cargo. Prior to our work the dogma in the transport field was that every organellar cargo would have specific receptors to directly recruit the transport machinery. It is now appreciated the organelle and mRNA hitchhiking on organelles is a found across the eukaryotic kingdom, including in human cells. We have discovered proteins, including the endosomal proteins PxdA and DipA (a phosphatase), which are required for organelle hitchhiking.

Current projects in the lab are aimed at determining the mechanism and physiological function of peroxisome hitchhiking on early endosomes.

Cell biology of secondary metabolism in filamentous fungi

PxdA, the gene required for peroxisome hitchhiking that we identified, is found exclusively in the Pezizomycotina sub-phylum of fungi. Pezizomycotina include A. nidulans, many plant and animal pathogens, and other economically and ecologically important fungal species. The Pezizomycotina are also notable for the number of secondary metabolites they produce. Examples include antibiotics such as penicillin, toxins such as aflatoxin, and metal harvesting siderophores. Most of the genes required for secondary metabolite biosynthesis are found in biosynthetic gene clusters (BGCs). A. nidulans has at least 75 BGCs. We recently discovered (in collaboration with the Keller lab at UW Madison) that changes in organelle trafficking impact secondary metabolite production in Aspergillus species (manuscript in preparation).

Current projects in the lab are aimed at determining the cell biology of secondary metabolite production.  

RNA recoding of molecular machines

Intelligent cephalopods extensively edit their mRNAs, which can lead to recoding (changes in amino acid sequence) and has been proposed to be adaptive for these organisms. The mRNAs encoding dynein and kinesin are some of the most highly recoded mRNAs in cephalopods, making the transport machinery an ideal model system for asking questions about the functional consequences of RNA recoding. Using wild squid, we discovered that RNA recoding alters kinesin motor properties in response to different seawater temperatures. Our results suggest that the squid “editome” is a nature-driven screen that can be mined not only to understand temperature adaptation, but also to guide the identification of functionally important regions of conserved proteins. In our most recent work, in collaboration with the Rangan lab at Johns Hopkins, we have identified the entire squid editome across three different ocean temperatures

Current projects in the lab focus on mining the squid editome to develop testable mechanistic hypotheses.