Abstract
Adaptation of molecular structure to the ligand chemistry and interaction with the cytoskeletal filament are key to understanding the mechanochemistry of molecular motors. Despite the striking structural similarity with kinesin-1, which moves towards plus-end, Ncd motors exhibit minus-end directionality on microtubules (MTs). Here, by employing a structure-based model of protein folding, we show that a simple repositioning of the neck-helix makes the dynamics of Ncd non-processive and minus-end directed as opposed to kinesin-1. Our computational model shows that Ncd in solution can have both symmetric and asymmetric conformations with disparate ADP binding affinity, also revealing that there is a strong correlation between distortion of motor head and decrease in ADP binding affinity in the asymmetric state. The nucleotide (NT) free-ADP (φ-ADP) state bound to MTs favors the symmetric conformation whose coiled-coil stalk points to the plus-end. Upon ATP binding, an enhanced flexibility near the head-neck junction region, which we have identified as the important structural element for directional motility, leads to reorienting the coiled-coil stalk towards the minus-end by stabilizing the asymmetric conformation. The minus-end directionality of the Ncd motor is a remarkable example that demonstrates how motor proteins in the kinesin superfamily diversify their functions by simply rearranging the structural elements peripheral to the catalytic motor head domain.
Highlights
Motor proteins in the kinesin superfamily play critical roles in a number of cellular processes such as vesicle and organelle transport, microtubule depolarization, chromosome and spindle organization during cell division [1,2,3]
While kinesin-1 has a C-terminal neck-helix followed by neck-linker and motor head (MH), Ncd has a N-terminal neck-helix that is linked to the MH via a short stretch of amino acids called neck-junction, which introduces slight variations in the contact maps
We found that only one of MHs is distorted towards its asymmetric conformation; the other MH still retains a conformation similar to the one in symmetric dimer
Summary
Motor proteins in the kinesin superfamily play critical roles in a number of cellular processes such as vesicle and organelle transport, microtubule depolarization, chromosome and spindle organization during cell division [1,2,3]. They convert chemical energy associated with ATP hydrolysis into mechanical work to undertake their specific tasks in the cell. In kinesin-1, NT-dependent affinity of the MH to MTs and order-disorder transition of the necklinker, which connects the MH with C-terminal neck-helix, were suggested as the key structural elements responsible for the motor directionality and head-to-head coordination [16,17,18,19,20,21,22,23,24].
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