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1.
Mol Microbiol ; 65(2): 347-62, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17573815

RESUMO

Kinesins from the bipolar (Kinesin-5) family are conserved in eukaryotic organisms and play critical roles during the earliest stages of mitosis to mediate spindle pole body separation and formation of a bipolar mitotic spindle. To date, genes encoding bipolar kinesins have been reported to be essential in all organisms studied. We report the characterization of CaKip1p, the sole member of this family in the human pathogenic yeast Candida albicans. C. albicans Kip1p appears to localize to the mitotic spindle and loss of CaKip1p function interferes with normal progression through mitosis. Inducible excision of CaKIP1 revealed phenotypes unique to C. albicans, including viable homozygous Cakip1 mutants and an aberrant spindle morphology in which multiple spindle poles accumulate in close proximity to each other. Expression of the C. albicans Kip1 motor domain in Escherichia coli produced a protein with microtubule-stimulated ATPase activity that was inhibited by an aminobenzothiazole (ABT) compound in an ATP-competitive fashion. This inhibition results in 'rigor-like', tight association with microtubules in vitro. Upon treatment of C. albicans cells with the ABT compound, cells were killed, and terminal phenotype analysis revealed an aberrant spindle morphology similar to that induced by loss of the CaKIP1 gene. The ABT compound discovered is the first example of a fungal spindle inhibitor targeted to a mitotic kinesin. Our results also show that the non-essential nature and implementation of the bipolar motor in C. albicans differs from that seen in other organisms, and suggest that inhibitors of a non-essential mitotic kinesin may offer promise as cidal agents for antifungal drug discovery.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Antifúngicos/farmacologia , Benzotiazóis/farmacologia , Candida albicans/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Adenosina Trifosfatases/análise , Candida albicans/enzimologia , Proteínas Fúngicas/análise , Genoma Fúngico/genética , Humanos , Proteínas Associadas aos Microtúbulos/análise , Proteínas Associadas aos Microtúbulos/genética , Mitose/efeitos dos fármacos , Fuso Acromático/enzimologia
2.
Nat Cell Biol ; 8(9): 913-23, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16906148

RESUMO

The budding yeast protein Kip3p is a member of the conserved kinesin-8 family of microtubule motors, which are required for microtubule-cortical interactions, normal spindle assembly and kinetochore dynamics. Here, we demonstrate that Kip3p is both a plus end-directed motor and a plus end-specific depolymerase--a unique combination of activities not found in other kinesins. The ATPase activity of Kip3p was activated by both microtubules and unpolymerized tubulin. Furthermore, Kip3p in the ATP-bound state formed a complex with unpolymerized tubulin. Thus, motile kinesin-8s may depolymerize microtubules by a mechanism that is similar to that used by non-motile kinesin-13 proteins. Fluorescent speckle analysis established that, in vivo, Kip3p moved toward and accumulated on the plus ends of growing microtubules, suggesting that motor activity brings Kip3p to its site of action. Globally, and more dramatically on cortical contact, Kip3p promoted catastrophes and pausing, and inhibited microtubule growth. These findings explain the role of Kip3p in positioning the mitotic spindle in budding yeast and potentially other processes controlled by kinesin-8 family members.


Assuntos
Cinesinas/metabolismo , Proteínas Associadas aos Microtúbulos/fisiologia , Microtúbulos/fisiologia , Proteínas Motores Moleculares/fisiologia , Proteínas de Saccharomyces cerevisiae/fisiologia , Fuso Acromático/fisiologia , Adenosina Trifosfatases/metabolismo , Ciclo Celular/fisiologia , Saccharomyces cerevisiae , Tubulina (Proteína)/metabolismo
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