Molecular Mechanisms of Axonal Transport
I received my Ph.D. in Biochemistry at the University of Minnesota in 1991, and did my post-doctoral research at the University of Pennsylvania. I have been on the faculty at the University of Vermont since 1994, with a primary appointment in Molecular Physiology & Biophysics and a secondary appointment in Biochemistry. I have been actively involved in the CMB Program, serving as the Program's Director from 2003-2006, and am currently the Director of Graduate Education for the College of Medicine.
Axonal transport is a critical process in neurons required for the efficient delivery of organelles, proteins, nucleic acids, and small molecules synthesized in the cell body to their site of function in distal regions of the axon. Defects in any one of the protein components in the axonal transport machinery, which includes molecular motor such as kinesin and dynein, the microtubule tracks they move on, a variety of adapter molecules that link motor proteins to their intracellular cargo, and regulatory MAPs (microtubule associated proteins) such as tau, result in serious and often lethal neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and ALS. Our lab in interested in understanding the interplay between post-translational modifications on both kinesin and tubulin (the protein subunits of microtubules), and different isoforms of tau, in regulating axonal transport under both normal and pathological conditions. We use a combination of molecular biology, fluorescence spectroscopy, and super-resolution single molecule imaging techniques, in both in vitro and in vivo systems, to achieve our goals. Recent results suggest that structural differences in the underlying microtubule lattice dictate tau’s ability to inhibit kinesin-mediated axonal transport in an isoform-specific manner (McVicker et al. (2011) J. Biol. Chem. 286:42873). Current projects are focused on 1.) elucidating the mechanism by which isoforms of tau differentially effect kinesin motility on varied microtubule lattice structures 2.) correlating the in vivo distribution of tau isoforms with different functional effects on both kinesin and microtubules, 3.) understanding the functional consequences of specific point mutations and post-translational modifications in tau associated with known neuronal pathologies, and 4.) examining the role of tau or phosphorylation of the kinesin motor domain in regulating bidirectional transport of intracellular cargo driven by different kinesin family members and cytoplasmic dynein.
Model of tau dynamics on the microtubule surface in axons.
Berger CL (2013) Breaking the millisecond barrier: single molecule motors wobble to find their next binding sites. Biophys J 104(6): 1219-20.
Decarreau JA, Chrin LR, Berger CL (2011) Loop 1 dynamics in smooth muscle myosin: isoform specific differences modulate ADP release. J Muscle Res Cell Motil 32(1): 49-61.
Decarreau JA, James NG, Chrin LR, Berger CL (2011) Switch I closure simultaneously promotes strong binding to actin and ADP in smooth muscle myosin. J Biol Chem 286(25): 22300-7.
Purcell TJ, Naber N, Franks-Skiba K, Dunn AR, Eldred CC, Berger CL, Málnási-Csizmadia A, Spudich JA, Swank DM, Pate E, Cooke R (2011) Nucleotide pocket thermodynamics measured by EPR reveal how energy partitioning relates myosin speed to efficiency. J Mol Biol 407(1): 79-91.
Robertson CI, Gaffney DP 2nd, Chrin LR, Berger CL (2005) Structural rearrangements in the active site of smooth-muscle myosin. Biophys J 89(3): 1882-92.
van Duffelen M, Chrin LR, Berger CL (2005) Kinetics of structural changes in the relay loop and SH3 domain of myosin. Biochem Biophys Res Commun 329(2): 563-72.
van Duffelen M, Chrin LR, Berger CL (2004) Nucleotide dependent intrinsic fluorescence changes of W29 and W36 in smooth muscle myosin. Biophys J 87(3): 1767-75.
Biophysical Journal Editorial Board
NIH MSFC Study Section Member
Biophysical Society Council
Department of Molecular Physiology & Biophysics
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Lab: Given E215
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