Mechanochemical tuning of a kinesin motor essential for malaria parasite transmission

Abstract

Plasmodium species cause malaria and kill hundreds of thousands annually. The microtubule-based motor kinesin-8B is required for development of the flagellated Plasmodium male gamete, and its absence completely blocks parasite transmission. To understand the molecular basis of kinesin-8B’s essential role, we characterised the in vitro properties of kinesin-8B motor domains from P. berghei and P. falciparum. Both motors drive ATP-dependent microtubule gliding, but also catalyse ATP-dependent microtubule depolymerisation. We determined these motors’ microtubule-bound structures using cryo-electron microscopy, which showed very similar modes of microtubule interaction in which Plasmodium-distinct sequences at the microtubule-kinesin interface influence motor function. Intriguingly however, P. berghei kinesin-8B exhibits a non-canonical structural response to ATP analogue binding such that neck linker docking is not induced. Nevertheless, the neck linker region is required for motility and depolymerisation activities of these motors. These data suggest that the mechanochemistry of Plasmodium kinesin-8Bs is functionally tuned to support flagella formation.

An axonemal intron splicing program sustains Plasmodium male development

“…Last, each assembled axoneme associates with a haploid nuclei to progressively protrude from the parasite plasma membrane, resulting in a free motile flagellum 10 . Mechanisms underlying the cytoplasmic assembly and exflagellation of axonemes in Plasmodium remain largely unknown, although the involvement of some conserved basal body and axonemal proteins has been described, including armadillo repeat protein PF16 41 , motor protein Kinesin8B 39 , 40 , 64 , basal body proteins SAS4 and SAS6 63 , 65 – 67 , and radial spoke protein RSP9 68 . It is possible that the Plasmodium had evolved novel mechanisms to fulfill the requirement for the axoneme.…”

New insights into the mechanochemical coupling mechanism of kinesin–microtubule complexes from their high-resolution structures

“…In kinesin-13, loop-2 is required for depolymerization activity [ 52 , 53 , 58 ], whereas Kip3 constructs without an elongated loop have severely impaired but not abolished microtubule depolymerization activity[ 32 , 59 ]. Different kinesin-8s also have different loop-2s ( Figure 4c ), and they also appear to interact with the microtubule in different manner [ 32 , 60 ] suggesting that this element may modulate motility and microtubule depolymerization activities in a different manner in different kinesin-8s. A summary of the mechanochemical cycles for kinesin-3s, kinesin-8s and kinesin-13s is presented in Figure 5 .…”

Photocontrollable DNA Walker-Based Molecular Circuit for the Tunable Detection of MicroRNA-21 Using Metal–Organic Frameworks as Label-Free Fluorescence Tags

“…DNA walkers, inspired by biological protein motors, have gained significant attention due to their capacity for autonomous movement and efficient amplification of cascade signals. − In a conventional DNA walker, the DNA walking strand is activated by fuel molecules to move continuously and gradually along the designated tracks using Brownian motion and chemical energy . Using various external stimulus, such as pH, exonucleases, DNAzymes, endonucleases, strand displacement reactions, and click chemistry, autonomous movement is initiated through DNA cleavage, contributing to remarkable signal amplification and strong recognition capabilities in biosensing. − It is worth noting that most DNA walker-based biosensors are designed with a fixed dynamic range and sensitivity, disregarding the significance of a tunable sensing performance that is crucial to fulfill the necessary requirements of detecting biomarkers in clinical samples with varying concentrations.…”