Three routes to suppression of the neurodegenerative phenotypes caused by kinesin heavy chain mutations.
Kinesin-1 is a motor protein that moves stepwise along microtubules by employing dimerized kinesin heavy chain (Khc) subunits that alternate cycles of microtubule binding, conformational change, and ATP hydrolysis. Mutations in the Drosophila Khc gene are known to cause distal paralysis and lethality preceded by the occurrence of dystrophic axon terminals, reduced axonal transport, organelle-filled axonal swellings, and impaired action potential propagation. Mutations in the equivalent human gene, Kif5A, result in similar problems that cause hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth type 2 (CMT2) distal neuropathies. By comparing the phenotypes and the complementation behaviors of a large set of Khc missense alleles, including one that is identical to a human Kif5A HSP allele, we identified three routes to suppression of Khc phenotypes: nutrient restriction, genetic background manipulation, and a remarkable intramolecular complementation between mutations known or likely to cause reciprocal changes in the rate of microtubule-stimulated ADP release by kinesin-1. Our results reveal the value of large-scale complementation analysis for gaining insight into protein structure-function relationships in vivo and point to possible paths for suppressing symptoms of HSP and related distal neuropathies.
Department of Molecular Cell and Developmental Biology, University of California, Santa Cruz, California 95064, USA.
Inna
I
Djagaeva
Debra J
DJ
Rose
Angeline
A
Lim
Chris E
CE
Venter
Katherine M
KM
Brendza
Pangkong
P
Moua
William M
WM
Saxton
D000483:Alleles; D000818:Animals; D001370:Axonal Transport / Q000235:genetics; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics; D005260:Female; D006801:Humans; D016547:Kinesins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D017434:Protein Structure, Tertiary
D029721:Drosophila Proteins; D050505:Mutant Proteins; D016547:Kinesins