Scientists Map Kinesin-2 Tail Structure To Understand Cargo Binding

For decades, scientists person known that centrifugal proteins for illustration kinesin-2 ferry captious cargo on microtubule "highways" wrong cells. But really these molecular vehicles place and hindrance to nan correct cargo remained a mystery. The caller study provides a cardinal portion of this puzzle by revealing nan atomic-level building of nan kinesin-2 tail and its relationship pinch cargo and adaptor proteins.

This study, led by Professor Nobutaka Hirokawa from Juntendo University pinch Dr. Masahide Kikkawa from nan University of Tokyo, Dr. Xuguang Jiang, a JSPS Postdoctoral Fellow, Dr. Radostin Danev from nan University of Tokyo, and Mr. Sotaro Ichinose from Gunma University, was published successful Science Advances connected October 24, 2025.

Using cryo-electron microscopy and molecular dynamics simulations, nan scientists reconstructed nan building of nan heterotrimeric kinesin-2 analyzable (KIF3A/KIF3B/KAP3) bound to nan cargo protein, adenomatous polyposis coli (APC). They discovered a unsocial structural motif successful nan tail region of KIF3A and KIF3B (termed hook-like adaptor and cargo-binding (HAC) domain) that acts arsenic a molecular "hook," enabling nan centrifugal to combine its adaptors and admit cargo pinch precocious specificity.

Our study has uncovered a antecedently chartless 'hook-like' structural element, nan HAC domain, successful nan tail of nan centrifugal macromolecule kinesin-2. This domain acts arsenic a molecular 'connector' that allows nan centrifugal to correctly admit and carrier its cargo wrong cells."

Nobutaka Hirokawa, Professor, Juntendo University

The HAC domain consists of a helix–β-hairpin–helix (H-βh-H) motif that forms a scaffold for nan adaptor macromolecule KAP3 and nan cargo macromolecule APC. The study revealed 4 chopped binding interfaces betwixt KIF3 and KAP3, pinch KIF3A playing a ascendant domiciled successful cargo recognition. The researchers besides recovered that nan HAC/KAP3 building resembles cargo-binding architectures of different centrifugal proteins, specified arsenic dynein and kinesin-1, suggesting a shared nickname framework.

"This find builds connected decades of investigation from our laboratory, which first identified and characterized nan complete family of mammalian kinesin centrifugal proteins successful nan 1980s and 1990s and later revealed really these molecular 'vehicles' move on nan cytoskeletal 'highways' of nan cell," Prof. Hirokawa said. "While we person agelong understood really these motors travel, nan remaining enigma was really they cognize what to carry. Our caller findings supply nan first atomic-level penetration into this 'logistics code' of cellular transport, nan molecular rules that let each centrifugal to admit and present its circumstantial cargo pinch singular precision."

The squad validated their structural exemplary utilizing cross-linking wide spectrometry, biochemistry, and neuronal compartment biology. They showed that nan HAC domain binds specifically to nan ARM repetition region of APC, a tumor suppressor macromolecule progressive successful neuronal RNA transport. Notably, KIF3A contributed nan mostly of nan binding energy, while KIF3B played a structural support role.

"Defects successful intracellular carrier are linked to a assortment of quality diseases, including neurodegenerative diseases, neurodevelopmental disorders, and ciliopathies," Prof. Hirokawa said. "Understanding really centrifugal proteins accurately admit and present their cargo provides a molecular ground for processing caller diagnostic and therapeutic approaches."

The study besides highlights nan imaginable for supplier find targeting motor-cargo interactions and nan creation of artificial carrier systems that mimic biologic logistics. However, nan authors statement that immoderate regions of nan macromolecule analyzable stay unresolved owed to structural flexibility, and further studies are needed to research cargo diverseness and regulatory mechanisms. This investigation marks a awesome measurement toward decoding nan cellular carrier strategy and knowing motor-driven cargo transportation successful neurons.