Neurodegeneration mutations in dynactin impair dynein-dependent nuclear migration.
Neurodegenerative disease in humans and mice can be caused by mutations affecting the microtubule motor dynein or its biochemical regulator, dynactin, a multiprotein complex required for dynein function (1-4). A single amino acid change, G59S, in the conserved cytoskeletal-associated protein glycine-rich (CAP-Gly) domain of the p150(glued) subunit of dynactin can cause motor neuron degeneration in humans and mice, which resembles ALS (2, 5-8). The molecular mechanism by which G59S impairs the function of dynein is not understood. Also, the relevance of the CAP-Gly domain for dynein motility has not been demonstrated in vivo. Here, we generate a mutant that is analogous to G59S in budding yeast, and show that this mutation produces a highly specific phenotype related to dynein function. The effect of the point mutation is identical to that of complete loss of the CAP-Gly domain. Our results demonstrate that the CAP-Gly domain has a critical role in the initiation and persistence of dynein-dependent movement of the mitotic spindle and nucleus, but it is otherwise dispensable for dynein-based movement. The need for this function appears to be context-dependent, and we speculate that CAP-Gly activity may only be necessary when dynein needs to overcome high force thresholds to produce movement.
Moore
Jeffrey K
JK
Department of Cell Biology and Physiology, Washington University, Saint Louis, MO 63110, USA.
Sept
David
D
Cooper
John A
JA
D002467:Cell Nucleus / Q000378:metabolism; D000072159:Dynactin Complex; D004398:Dyneins; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009068:Movement; D020125:Mutation, Missense; D009410:Nerve Degeneration / Q000235:genetics*; D021122:Protein Subunits; D008941:Spindle Apparatus / Q000378:metabolism; D015003:Yeasts / Q000235:genetics
C000606360:DCTN1 protein, human; C000606364:Dctn1 protein, mouse; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D021122:Protein Subunits; D004398:Dyneins