Connecting tubules: mechanisms of endoplasmic reticulum membrane fusion

Abstract

Atlastins (ATLs) are integral dynamin-like GTPases that are critical for the formation and maintenance of the endoplasmic reticulum (ER) network, one of the most complex and essential organelles in eukaryotic cells. The ER, which is composed of interconnected tubules and sheets, serves vital functions, including calcium storage, protein and lipid synthesis, and inter-organelle communication. Homotypic membrane fusion, mediated by ATLs, ensures the tubular structure of the ER by generating and stabilizing three-way junctions. Humans express three ATL paralogs, called ATL1, ATL2, and ATL3, which have distinct expression patterns and regulatory mechanisms. Mutations in these proteins are linked to hereditary sensory neuropathies and hereditary spastic paraplegia, highlighting their critical importance in cellular and neuronal health. Here, we review recent studies providing insights into how ATLs are regulated by their N- and C-terminal extensions, as well as how extrinsic factors potentially regulate the activities of ATLs to establish and maintain the normal ER structure.

Keywords: GTPases; endoplasmic reticulum; membrane fusion; organelle biogenesis.

Figure 1:. Domain organization of human ATLs and related proteins.

Human ATL1, human ATL2, human ATL3, Drosophila ATL (dATL), Saccharomyces cerevisiae Sey1p, and Arabidopsis thaliana RHD3 are shown. The protein diagram shows the number of amino acid residues and where specific domains are located within the structure. While the three human paralogs are organized into five distinct segments (shown as colored cylinders), the remaining proteins are subdivided into four segments. From start to end, the structure consists of an N-terminus of varying length shown in black, a highly preserved GTPase domain shown in blue, a middle domain shown in orange, two consecutive TMDs shown in purple, and a C-terminus of varying length shown in green or a combination of yellow and light green.

Figure 2:. Intrinsic and extrinsic modes of ATL regulation.