6f9i
Crystal structure of KLC2 bound to the second tryptophan-acidic motif peptide from calsyntenin-1Crystal structure of KLC2 bound to the second tryptophan-acidic motif peptide from calsyntenin-1
Structural highlights
Function[CSTN1_MOUSE] Induces KLC1 association with vesicles and functions as a cargo in axonal anterograde transport. Complex formation with APBA2 and APP, stabilizes APP metabolism and enhances APBA2-mediated suppression of beta-APP40 secretion, due to the retardation of intracellular APP maturation. In complex with APBA2 and C99, a C-terminal APP fragment, abolishes C99 interaction with PSEN1 and thus APP C99 cleavage by gamma-secretase, most probably through stabilization of the direct interaction between APBA2 and APP. As intracellular fragment AlcICD, suppresses APBB1-dependent transactivation stimulated by APP C-terminal intracellular fragment (AICD), most probably by competing with AICD for APBB1-binding. May modulate calcium-mediated postsynaptic signals.[1] [2] Publication Abstract from PubMedKinesin-1 transports numerous cellular cargoes along microtubules. The kinesin-1 light chain (KLC) mediates cargo binding and regulates kinesin-1 motility. To investigate the molecular basis for kinesin-1 recruitment and activation by cargoes, we solved the crystal structure of the KLC2 tetratricopeptide repeat (TPR) domain bound to the cargo JIP3. This, combined with biophysical and molecular evolutionary analyses, reveals a kinesin-1 cargo binding site, located on KLC TPR1, which is conserved in homologs from sponges to humans. In the complex, JIP3 crosslinks two KLC2 TPR domains via their TPR1s. We show that TPR1 forms a dimer interface that mimics JIP3 binding in all crystal structures of the unbound KLC TPR domain. We propose that cargo-induced dimerization of the KLC TPR domains via TPR1 is a general mechanism for activating kinesin-1. We relate this to activation by tryptophan-acidic cargoes, explaining how different cargoes activate kinesin-1 through related molecular mechanisms. Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3.,Cockburn JJB, Hesketh SJ, Mulhair P, Thomsen M, O'Connell MJ, Way M Structure. 2018 Aug 23. pii: S0969-2126(18)30257-0. doi:, 10.1016/j.str.2018.07.011. PMID:30197037[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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