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<p>Product inhibition is a common regulatory feature of ATPases, in which the hydrolysis product suppresses further enzymatic activity. Kinesins are microtubule-dependent ATPases that typically undergo inhibition by ADP, the product of ATP hydrolysis. Here, we show that the <i>Caenorhabditis elegans</i> kinesin-3 KLP-6 is unusually resistant to product inhibition by ADP and continues to move along microtubules at an unreduced speed even in the presence of high ADP concentrations. Kinetic measurements of the Michaelis constant for Mg·ATP (<i>K</i><sub>M</sub>) and the inhibition constant for Mg·ADP (<i>K</i><sub>I</sub>) revealed a <i>K</i><sub>I</sub><i>/K</i><sub>M</sub> ratio of 44.9 for KLP-6, markedly higher than the ratio of 1.3 for the well-studied kinesin-3 KIF1A, indicating substantially greater selectivity for ATP over ADP. Sequence comparison identified a unique region in the α2a helix of KLP-6. Replacing this segment with the corresponding KIF1A sequence abolished the elevated ATP/ADP selectivity, demonstrating that this region is required for resistance to product inhibition. Molecular dynamics simulations further showed that the α2a helix is less conformationally stable in the ADP-bound state than in the ATP-bound state, providing a structural basis for nucleotide discrimination. Together, our findings reveal a molecular mechanism underlying nucleotide selectivity in kinesins.</p>

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KLP-6 is a kinesin superfamily protein resistant to ADP inhibition

  • 期刊论文

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  • 发表日期：

    2026年5月5日

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  • Tomoki Kita,
  • Taisei Watanabe,
  • Shinsuke Niwa

摘要

Product inhibition is a common regulatory feature of ATPases, in which the hydrolysis product suppresses further enzymatic activity. Kinesins are microtubule-dependent ATPases that typically undergo inhibition by ADP, the product of ATP hydrolysis. Here, we show that the Caenorhabditis elegans kinesin-3 KLP-6 is unusually resistant to product inhibition by ADP and continues to move along microtubules at an unreduced speed even in the presence of high ADP concentrations. Kinetic measurements of the Michaelis constant for Mg·ATP (KM) and the inhibition constant for Mg·ADP (KI) revealed a KI/KM ratio of 44.9 for KLP-6, markedly higher than the ratio of 1.3 for the well-studied kinesin-3 KIF1A, indicating substantially greater selectivity for ATP over ADP. Sequence comparison identified a unique region in the α2a helix of KLP-6. Replacing this segment with the corresponding KIF1A sequence abolished the elevated ATP/ADP selectivity, demonstrating that this region is required for resistance to product inhibition. Molecular dynamics simulations further showed that the α2a helix is less conformationally stable in the ADP-bound state than in the ATP-bound state, providing a structural basis for nucleotide discrimination. Together, our findings reveal a molecular mechanism underlying nucleotide selectivity in kinesins.