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Mosalaganti, Shyamal; Keller, Jenny; Altenfeld, Anika; Winzker, Michael; Rombaut, Pascaline; Saur, Michael; Petrovic, Arsen; Wehenkel, Annemarie; Wohlgemuth, Sabine; Müller, Franziska; Maffini, Stefano; Bange, Tanja; Herzog, Franz; Waldmann, Herbert; Raunser, Stefan; Musacchio, Andrea (2017): Structure of the RZZ complex and molecular basis of its interaction with Spindly. In: Journal of Cell Biology, Vol. 216, Nr. 4: S. 961-981
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Abstract

Kinetochores are macromolecular assemblies that connect chromosomes to spindle microtubules (MTs) during mitosis. The metazoan-specific approximate to 800-kD ROD-Zwilch-ZW10 (RZZ) complex builds a fibrous corona that assembles on mitotic kinetochores before MT attachment to promote chromosome alignment and robust spindle assembly checkpoint signaling. In this study, we combine biochemical reconstitutions, single-particle electron cryomicroscopy, cross-linking mass spectrometry, and structural modeling to build a complete model of human RZZ. We find that RZZ is structurally related to self-assembling cytosolic coat scaffolds that mediate membrane cargo trafficking, including Clathrin, Sec13-Sec31, and alpha beta'epsilon-COP. We show that Spindly, a dynein adaptor, is related to BicD2 and binds RZZ directly in a farnesylation-dependent but membrane-independent manner. Through a targeted chemical biology approach, we identify ROD as the Spindly farnesyl receptor. Our results suggest that RZZ is dynein's cargo at human kinetochores.