title: Allostery Wiring Map for Kinesin Energy Transduction and Its Evolution.
abstract: How signals between the kinesin active and cytoskeletal binding sites are transmitted is an open question and an allosteric question. By extracting correlated evolutionary changes within 700+ sequences, we built a model of residues that are energetically coupled and that define molecular routes for signal transmission. Typically, these coupled residues are located at multiple distal sites and thus are predicted to form a complex, non-linear network that wires together different functional sites in the protein. Of note, our model connected the site for ATP hydrolysis with sites that ultimately utilize its free energy, such as the microtubule-binding site, drug-binding loop 5, and necklinker. To confirm the calculated energetic connectivity between non-adjacent residues, double-mutant cycle analysis was conducted with 22 kinesin mutants. There was a direct correlation between thermodynamic coupling in experiment and evolutionarily derived energetic coupling. We conclude that energy transduction is coordinated by multiple distal sites in the protein rather than only being relayed through adjacent residues. Moreover, this allosteric map forecasts how energetic orchestration gives rise to different nanomotor behaviors within the superfamily.
authors: From the Department of Biochemistry and Molecular Biology, Louisiana State University School of Medicine & Health Sciences Center, New Orleans, Louisiana 70112.
authors: Jessica
authors: J
authors: Richard
authors: From the Department of Biochemistry and Molecular Biology, Louisiana State University School of Medicine & Health Sciences Center, New Orleans, Louisiana 70112.
authors: Elizabeth D
authors: ED
authors: Kim
authors: From the Department of Biochemistry and Molecular Biology, Louisiana State University School of Medicine & Health Sciences Center, New Orleans, Louisiana 70112.
authors: Hoang
authors: H
authors: Nguyen
authors: From the Department of Biochemistry and Molecular Biology, Louisiana State University School of Medicine & Health Sciences Center, New Orleans, Louisiana 70112.
authors: Catherine D
authors: CD
authors: Kim
authors: From the Department of Biochemistry and Molecular Biology, Louisiana State University School of Medicine & Health Sciences Center, New Orleans, Louisiana 70112 skim3@lsuhsc.edu.
authors: Sunyoung
authors: S
authors: Kim
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D019143:Evolution, Molecular; D006801:Humans; D006868:Hydrolysis; D016547:Kinesins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation
chemical_list: D000255:Adenosine Triphosphate; D016547:Kinesins
keywords: ATP hydrolysis; double-mutant cycle analysis; enzyme mechanism; kinesin; long-range thermodynamic coupling; mechanotransduction; molecular motor; mutagenesis; residue co-evolution; statistical coupling analysis