title: The origin of minus-end directionality and mechanochemistry of Ncd motors.
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.
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.
authors.forename: Biman
authors.initials: B
authors.lastname: Jana
authors.forename: Changbong
authors.initials: C
authors.lastname: Hyeon
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001696:Biomechanical Phenomena; D019295:Computational Biology; D003198:Computer Simulation; D016547:Kinesins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D008956:Models, Chemical; D008958:Models, Molecular; D025341:Principal Component Analysis; D011487:Protein Conformation
chemical_list: D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D016547:Kinesins