9.B.113 The Collagen Secretory Protein, Mia3 (Mia3) Family
Melanoma inhibitory activity member 3 (MIA3/TANGO1) is an evolutionarily conserved endoplasmic reticulum resident transmembrane protein. In vitro studies have shown that it is required for the loading of collagen VII into COPII-coated transport vesicles. Wilson et al. (2011) showed that mice lacking Mia3 are defective for the secretion of numerous collagens, including collagens I, II, III, IV, VII, and IX. Collagen deposition by these cell types is abnormal, and the extracellular matrix composition is compromised. These changes are associated with intracellular accumulation of collagen and the induction of a strong unfolded protein response, primarily within the developing skeleton. Chondrocyte maturation and bone mineralization are severely compromised in Mia3-null embryos, leading to dwarfism and neonatal lethality. Thus, Mia3 may be required for the efficient secretion of all collagens in higher organisms (Wilson et al., 2011).
Secretory proteins are exported from special domains of the endoplasmic reticulum (ER) termed ER exit sites, via COPII-coated carriers. Maeda et al. 2019 showed that TANGO1 and Sec16 cooperatively organize mammalian ER exit sites for efficient secretion. Domains are abundant in transmembrane complexes (TANGO1/cTAGE5/Sec12 = 9.B.113.1.1/9.B.113.1.4/Q9HCU5 with 417 aas and 3 TMSs, one N-terminal and two close together further on) juxtaposed to Sec16A (O15027). This domain can be distinguished from the inner and the outer coats of COPII proteins within each mammalian ER exit site. Cargoes are partially concentrated in the domain for secretion. These observations suggest that mammalian ER exit sites compartmentalize proteins according to their function in COPII vesicle formation (Maeda et al. 2019). Sec23A (Q15436, 765 aas) may be a component of athe coat protein complex II (COPII).
TANGO1 organizes membranes at the interface of the endoplasmic reticulum (ER) and ERGIC/Golgi. It corrals retrograde membranes at ER exit sites to create an export conduit. The retrograde membrane is, in itself, an anterograde carrier (Raote et al. 2020). This mode of forward transport necessitates a mechanism to prevent membrane mixing between the ER and the retrograde membrane. TANGO1 has an unusual membrane helix organisation, composed of one membrane-spanning helix (TM) and another that penetrates the inner leaflet (IM). Raote et al. 2020 reconstituted these membrane helices in model membranes and showed that TM and IM together reduce the flow of lipids at a region of defined shape. They also found that the helices align TANGO1 around an ER exit site. Possibly this is a mechanism to prevent membrane mixing during TANGO1-mediated transfer of bulky secretory cargos from the ER to the ERGIC/Golgi via a tunnel.
References:
The endoplasmic reticulum (ER) membrane melanoma inhibitory activity, member3 (Mia 3; TANGO1) (1930 aas; 3 TMSs), one N-terminal and two together near the C-terminus. It is required for collagen and protein secretion in mice (Wilson et al., 2011; Ishikawa et al. 2016). (It resembles 1.I.1.1.1 with the latter showing many repeats that are homologous to residues 1230-1630 in Mia3).
Animals
Mia3 of Mus musculus (Q8BI84)
Transport and golgic organization protein 1, Mia1 or TANGO1, of 1907 aas and 3 potential TMSs, one N-terminal and two closely positioned at about residue 1200. It plays a role in the transport of cargos that are too large to fit into COPII-coated vesicles and require specific mechanisms to be incorporated into membrane-bound carriers and exported from the endoplasmic reticulum (ER). This protein is required for collagen VII (COL7A1) secretion by loading COL7A1 into transport carriers. It may participate in cargo loading of COL7A1 at ER exit sites by binding to COPII coat subunits Sec23/24 and guiding SH3-bound COL7A1 into a growing carrier. It does not play a role in global protein secretion and is apparently specific to COL7A1 cargo loading. It is required for the secretion of lipoproteins by participating in their export from the ER (Santos et al. 2016). It is localised at ER exit sites, where it binds bulky cargo within the ER lumen and recruits membranes from the ER Golgi intermediate compartment to create an exit route for their export. Lekszas et al. 2020 reported the first TANGO1-associated syndrome in humans. A synonymous substitution results in exon eight skipping, ultimately leading to a truncated TANGO1 protein,and it causes disease that involves severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies revealed that the corresponding truncated TANGO1 protein is dispersed in the ER, and its expression in cells with intact endogenous TANGO1 impairs cellular collagen I secretion (Lekszas et al. 2020).
Mia1 of Homo sapiens
Transport and Golgi organization protein, TANGO, of 1430 aas and probably 3 TMSs, one N-terminal and two in the middle of the protein. It is required for protein secretion (Bard et al. 2006) and may participate in cargo loading by binding to COPII coat subunits and guiding SH3-bound proteins into a growing carrier (Bard et al. 2006). At basal transitional ER sites in follicle epithelial cells, it mediates the exit of basal membrane proteins such as Vkg, LanB1 and Trol, from the endoplasmic reticulum (ER) to basal Golgi clusters (Lerner et al. 2013). Homologues may exist in all eukaryotes and function in similar capacities (Elliott et al. 2020; Saito and Maeda 2019).
TANGO of Drosophila melanogaster
Mia2 or cTAGE5 of 1412 aas and 3 TMSs, one N-terminal and two closely together in the middle of the protein. It plays a role in the transport of cargos that are too large to fit into COPII-coated vesicles and require specific mechanisms to be incorporated into membrane-bound carriers and exported from the endoplasmic reticulum (Santos et al. 2016).
Mia2 of Homo sapiens