Eukaryotic cells use microtubule-based transport to accomplish intracellular organelle movement, cell division, and possibly cellular morphogenesis. These events require the activities of microtubule-motor proteins such as kinesin. In this proposal we describe experiments designed to understand how kinesin converts chemical energy into mechanical force, how kinesin attaches to the elements that it moves, what structural features of kinesin are essential for in vivo function, and where kinesin fits in the scheme of all MT-based movements, some of which might be generated by kinesin-like motors. To accomplish these goals, we will: 1) continue our studies of the elements of the kinesin heavy chain motor domain needed for force generation and develop methods for large-scale production of the kinesin motor domain for use in high-resolution structural studies; 2) begin analyses of proteins with which the kinesin heavy chain tail interacts in order to attach to cellular cargoes. 3) alter kinesin heavy chain in defined ways and introduce these altered molecules back into the organism for study in vivo; and 4) analyze five new genes that we have recently discovered that appear to encode kinesin-like proteins. In toto, our investigations will reveal how one particular microtubule motor functions and will begin to unravel the range of functions and strategies used by eukaryotes to accomplish microtubule-based movements.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM035252-08
Application #
3287684
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1985-08-30
Project End
1995-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Gunawardena, Shermali; Yang, Ge; Goldstein, Lawrence S B (2013) Presenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo. Hum Mol Genet 22:3828-43
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Falzone, Tomás L; Gunawardena, Shermali; McCleary, David et al. (2010) Kinesin-1 transport reductions enhance human tau hyperphosphorylation, aggregation and neurodegeneration in animal models of tauopathies. Hum Mol Genet 19:4399-408
Abe, Namiko; Almenar-Queralt, Angels; Lillo, Concepcion et al. (2009) Sunday driver interacts with two distinct classes of axonal organelles. J Biol Chem 284:34628-39
Shah, Sameer B; Nolan, Rhiannon; Davis, Emily et al. (2009) Examination of potential mechanisms of amyloid-induced defects in neuronal transport. Neurobiol Dis 36:11-25
Falzone, Tomás L; Stokin, Gorazd B; Lillo, Concepción et al. (2009) Axonal stress kinase activation and tau misbehavior induced by kinesin-1 transport defects. J Neurosci 29:5758-67
Stokin, Gorazd B; Almenar-Queralt, Angels; Gunawardena, Shermali et al. (2008) Amyloid precursor protein-induced axonopathies are independent of amyloid-beta peptides. Hum Mol Genet 17:3474-86
Xia, Chun-Hong; Roberts, Elizabeth A; Her, Lu-Shiun et al. (2003) Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A. J Cell Biol 161:55-66
Gunawardena, Shermali; Her, Lu-Shiun; Brusch, Richard G et al. (2003) Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40:25-40
Ji, Jun-Yuan; Haghnia, Marjan; Trusty, Cory et al. (2002) A genetic screen for suppressors and enhancers of the Drosophila cdk1-cyclin B identifies maternal factors that regulate microtubule and microfilament stability. Genetics 162:1179-95

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