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Abstract:
The RZZ complex recruits dynein to kinetochores. We investigated
structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH,
and ZW10) in vitro, in vivo, and in silico. We identify
neuroblastoma-amplified gene (NAG), a ZW10 binder, as a ROD homolog. ROD
and NAG contain an N-terminal beta propeller followed by an alpha
solenoid, which is the architecture of certain nucleoporins and vesicle
coat subunits, suggesting a distant evolutionary relationship. ZW10
binding to ROD and NAG is mutually exclusive. The resulting ZW10
complexes (RZZ and NRZ) respectively contain ZWILCH and RINT1 as
additional subunits. The X-ray structure of ZWILCH, the first for an RZZ
subunit, reveals a novel fold distinct from RINT1's. The evolutionarily
conserved NRZ likely acts as a tethering complex for retrograde
trafficking of COPI vesicles from the Golgi to the endoplasmic
reticulum. The RZZ, limited to metazoans, probably evolved from the NRZ,
exploiting the dynein-binding capacity of ZW10 to direct dynein to
kinetochores.
