13 March 2018 One Ring to Rule Collagen Export

Multicolour super-resolution imaging of the TANGO1 complex (left) and model explaining collagen transport (centre & right)

New insights on how large molecules such as collagens are exported published in eLife. Research performed in the framework of a BIST Ignite grant (eTANGO), jointly awarded to Felix Campelo at the Single Molecule Biophotonics group led by ICREA Professor at ICFO Maria Garcia-Parajo, and Ishier Raote at the ICREA Professor Vivek Malhotra lab at the CRG, demonstrates how a protein called TANGO1 assembles in a coordinated way the molecular machinery required to export collagen at the endoplasmatic reticulum. The work has been recently published in eLife.

Over the past four decades, we have witnessed the discovery of the molecular machinery cells use to secrete proteins to the extracellular space, which led to Rothman, Schekman and Südhof to be awarded with the Nobel Prize in Physiology or Medicine in 2013. However, these discoveries do not reveal how cells secrete bulky proteins such as collagens, which constitute up to 25% of our dry body weight. Collagens are rigid, large proteins (of up to 400 nm in length) that cannot be accommodated into the canonical, regularly-sized vesicular carriers (of 60-90 nm in diameter) that shuttle proteins away from the endoplasmic reticulum (ER), the place where these secretory proteins are synthesized. How are then collagens exported from the ER? This is an issue of fundamental importance because of the involvement of collagens in cell and tissue organization, bone mineralization and skin biogenesis. A major step towards understanding collagen export was provided a few years ago with the discovery that an ER protein, named TANGO1, acts as a guide to specifically load collagens into transport carriers.

The sites of collagen export at the ER membrane domains were recently visualized with high spatial resolution by super-resolution stimulated emission depletion (STED) microscopy. These studies showed for the first time that TANGO1 is organized as a ring of ~200 nm in size. However, what is the function and molecular identity of these TANGO1 rings? How do they cooperate to generate a transport carrier commensurate with the large size of bulky collagens? Felix Campelo and colleagues used a battery of state-of-the-art genetic tools with superresolution optical nanoscopy techniques and physical models to elucidate the molecular and physical mechanisms by which TANGO1 organizes the machinery required for efficient export of collagens. They identified different sets of interactions required for the assembly of functional collagen export domains, including (i) lateral self-interaction of TANGO1 and TANGO1-like proteins, (ii) transverse interaction of TANGO1 with the vesicle formation machinery, and (iii) tethering of small vesicles to act as a membrane source for the growth of a large collagen-containing carrier. Overall, these results suggest a mechanism whereby TANGO1 assembles into a functional ring, which selectively gathers and organizes collagen, remodels the ER export machinery, and recruits membranes for the formation of a collagen-containing export megacarrier. Remarkably, mutations in collagens are linked to the pathogenesis of a vast number of human diseases, including arterial aneurysms, muscular dystrophy, and epidermolysis bullosa ¬–a genetic disease resulting from attachment defects between the epidermis and dermis of the skin. Hence, these findings will allow us to design chemicals to control collagen homeostasis and thus a means to alleviate some of the deleterious effect of these human pathologies.