Coatopathies: Genetic Disorders of Protein Coats

Abstract

Protein coats are supramolecular complexes that assemble on the cytosolic face of membranes to promote cargo sorting and transport carrier formation in the endomembrane system of eukaryotic cells. Several types of protein coats have been described, including COPI, COPII, AP-1, AP-2, AP-3, AP-4, AP-5, and retromer, which operate at different stages of the endomembrane system. Defects in these coats impair specific transport pathways, compromising the function and viability of the cells. In humans, mutations in subunits of these coats cause various congenital diseases that are collectively referred to as coatopathies. In this article, we review the fundamental properties of protein coats and the diseases that result from mutation of their constituent subunits.

Keywords: clathrin; coatomer; neurological disorders; protein trafficking; rare diseases; sorting signals.

Figure 1.

Schematic representation of the endomembrane system of a eukaryotic cell showing the location of protein coats discussed in this review. Arrows indicate the direction of sorting mediated by each coat. Some of these directions are well established, whereas others should be considered provisional. The plasma membrane is represented as having two distinct domains (1 and 2), as is the case in polarized cells. Although not represented here, AP-2 also plays a role in endocytosis from both plasma membrane domains. The term “tubular endosomal network” (TEN) is used to refer to a collection of tubules emanating from vacuolar endosomes.

Figure 2.

Electron micrographs of coated vesicles and tubules formed in vitro by assembly of purified coat components on liposomes or membrane fractions. (A) Thin-section electron microscopy of clathrin-coated vesicles formed from liposomes (Dannhauser and Ungewickell, 2012). (B) Section from a cryoelectron tomogram of COPI vesicles formed from giant unilamellar vesicles (Faini et al., 2012). (C) Thin-section electron microscopy of COPII vesicles formed from a membrane fraction (Barlowe et al., 1994). (D) Section from a cryoelectron tomogram of a yeast retromer complex assembled on liposome tubules (Kovtun et al., 2018). In all cases, notice the appearance of coats as electron-dense deposits on the surface of vesicles and tubules. Images reproduced with permission from the publishers.

Figure 3.

Schematic representation of prototypic coats assembled on membrane buds. (A) AP-2. (B) COPII. (C) COPI. (D) Retromer. The coats represented in this figure are those for which there is both X-ray crystallographic and structural electron microscopy data. The schemes highlight some of the features of these coats but are not intended to be accurate representations of their three-dimensional structures. AP-2, COPII and retromer are shown as having membrane-proximal (inner/adaptor) and membrane-distal (outer/scaffold) layers. Despite the homology of COPI subunits to those of AP-2/clathrin, the F- and B-subcomplexes are not arranged as layers but parts of both subcomplexes are in close proximity to the membrane. The retromer complex represented in this figure corresponds to that containing sorting nexin 3 (SNX3), but there are other forms of retromer containing SNX27 and, in yeast, Vps5 and Vps17. For the complexes represented in this figure, cargo recognition is mainly mediated by AP-2, the B-subcomplex, SEC23-SEC24 and SNX3-VPS26, respectively, although additional modes of cargo recognition are possible. More details of the protein composition of AP complexes and COPI-F are shown in Figure 4.

Figure 4.

Schematic representation of AP complexes, COPI-F and ARH. The schemes represent the “unlocked” membrane-bound form of AP complexes and COPI-F. Subunit names are indicated. Homologous subunits are depicted in the same color.