# Getting Sugar Coating Right! The Role of the Golgi Trafficking Machinery in Glycosylation
## 3 Membrane Trafficking Machinery
### Tethers (MTCs and Coiled-Coil Tethers)
#### 3.1.2 Multisubunit Tethering Complexes  
The conserved oligomeric Golgi (COG) complex is the major CATCHR (complexes associated with tethering containing helical rods) vesicle tethering, hetero-octameric complex in the Golgi vicinity, with subunits COG1-COG8 [128; 129; 130; 131]. It is divided into two subcomplexes named Lobe A (COGs 1-4) and Lobe B (COGs 5-8) with an interaction between COG1 and COG8 [128; 132; 133; 134]. The COG complex appears to interact with all types of trafficking facilitators throughout the Golgi, such as SNAREs, SNARE-interacting proteins, Rabs, coiled-coil tethers, and vesicular coats [134]. The array of protein interactions suggests that COG, generally, orchestrates sequential processes triggered by activated Rab proteins beginning with vesicle attachment and concluding with the assembly of SNARE complexes [135]. Different COG subunits assigned as different \"interaction hubs\" such as COG2 and COG3 act as \"tether hubs,\" COG2, COG3, and COG4 act as \"coat and motor hubs,\" COG4, COG5, and COG6 act as \"Rab hubs,\" and COG4, COG6, COG7, and COG8 act as \"SNARE hubs.\" The COG complex has two potential conformations which were uncovered by electron microscopy (EM) in fixed and unfixed conditions. When unfixed, the COG complex has an extended and seemingly flexible structure (approximately 50-75 nm long) with multiple elongated, curved arms with globular or 'hook like' ends, whereas when fixed, the COG complex has a more globular appearance (\(\sim\)37 nm in length) with rod-like connections between the two main lobes [128; 129; 130; 135; 136]. The exact conformation of the membrane-bound COG complex is unknown; however, live-cell super-resolution microscopy studies indicate that COG lobe A is preferentially Golgi bound, while lobe B is localized on vesicles [137]. COG mainly acts as a vesicular tether in retrograde intra-Golgi trafficking and recycles Golgi resident proteins (such as glycosylation enzymes) to maintain proper glycosylation of secretory proteins [138; 139; 140; 141]. Recent studies on a complete set of COG subunit KOs in HEK293T cells, using a CRISPR-Cas9 approach, provided further insights into the COG's function at the Golgi [142]. All COG deficient cells had glycosylation defects implicating the role of both lobes of the COG complex in maintaining glycosylation fidelity. Furthermore, each COG subunit-deficient cell line had defects in Golgi morphology, retrograde trafficking, sorting, and secretion, and accumulated enlarged endolysosomal structures (EELSs) [143; 144]; however, the severity of these defects varied among subunits [142]. Almost one-third of the patients with congenital defects in the Golgi glycosylation have mutations in one of the subunits of the COG complex and this type of CDG is termed COG-CDG [10; 145] (Table 1). Over a hundred individuals with 31 different mutations in different COG subunits (except COG3) have been identified to date, presenting heterogeneous clinical features and cellular phenotypes. COG-CDGs are rare and incurable diseases that belong to a group of autosomal recessive disorders and multi-systemic disorders with several distinguishable symptoms that include global developmental defects, includingdysmorphic features, microcephaly, and failure to thrive. These deficits are often accompanied by liver and neurological impairment [13]. Lobe A (COG) mutations are proposed to be more deleterious than lobe B mutations [146], but it is still unclear because of the small number of known mutations and the lack of robust data on these patients. It has been reported that COG1 and COG4 patients present milder problems in comparison to COG7 and COG8 patients [147]. Among all the COG-CDGs, COG7 mutation is the most severe and COG6-CDG is nearly severe as 50% of the patients died within the first two years of life [148].