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Cog5–Cog7 crystal structure reveals interactions essential for the function of a multisubunit tethering complex

Significance In all eukaryotes, the docking and fusion of the vesicles that mediate intracellular trafficking requires multisubunit tethering complexes (MTCs). MTCs are thought to mediate the initial interaction between the vesicle and its target membrane and to orchestrate the assembly of the protein fusion machinery. The largest family of MTCs—of which the conserved oligomeric Golgi (COG) complex is a well-studied member—has been recalcitrant to structural characterization, presumably owing to the size and intrinsic flexibility of the complexes and their constituent subunits. Here we report the initial characterization of subunit interactions within the COG complex by X-ray crystallography. Mutations in the conserved intersubunit interface may be responsible for human congenital glycosylation disorders. The conserved oligomeric Golgi (COG) complex is required, along with SNARE and Sec1/Munc18 (SM) proteins, for vesicle docking and fusion at the Golgi. COG, like other multisubunit tethering complexes (MTCs), is thought to function as a scaffold and/or chaperone to direct the assembly of productive SNARE complexes at the sites of membrane fusion. Reflecting this essential role, mutations in the COG complex can cause congenital disorders of glycosylation. A deeper understanding of COG function and dysfunction will likely depend on elucidating its molecular structure. Despite some progress toward this goal, including EM studies of COG lobe A (subunits 1–4) and higher-resolution structures of portions of Cog2 and Cog4, the structures of COG’s eight subunits and the principles governing their assembly are mostly unknown. Here, we report the crystal structure of a complex between two lobe B subunits, Cog5 and Cog7. The structure reveals that Cog5 is a member of the complexes associated with tethering containing helical rods (CATCHR) fold family, with homology to subunits of other MTCs including the Dsl1, exocyst, and Golgi-associated retrograde protein (GARP) complexes. The Cog5–Cog7 interaction is analyzed in relation to the Dsl1 complex, the only other CATCHR-family MTC for which subunit interactions have been characterized in detail. Biochemical and functional studies validate the physiological relevance of the observed Cog5–Cog7 interface, indicate that it is conserved from yeast to humans, and demonstrate that its disruption in human cells causes defects in trafficking and glycosylation.