Atlastin

ATLs maintain the ER tubular network via homotypic fusion. ATLs have a conserved domain structure consisting of a globular G domain, a three-helix bundle,[3] two transmembrane domains, and an amphipathic helix.[4] The ATL fusion cycle consists of two ATL monomers in opposing membranes binding GTP, which induces trans G domain dimerization and a crossing over of the three-helix bundle.[3][5][6] Crossover and subsequent insertion of the amphipathic helix into the lipid bilayer triggers lipids to mix for fusion.[4][7] Lastly, GTP is hydrolyzed driving the dimer to disassembly and resetting the fusion machinery.[8][9]

While most of the human ATL protein structure is conserved between paralogs,[10] the proteins have non-conserved N- and C-termini with the C-termini of ATL1 and ATL2 being autoinhibitory.[11] ATL1 has been shown to interact with a range of proteins including spastin[1] and REEP1,[12] with spastin enhancing ATL1 fusion activity in vitro.[13] ATL1 and ATL2 have also been observed as interacting with ER protein TMCC3,[14] and ATL3 with nonstructural viral proteins,[15] however it is not currently known how these interactions modulate protein function.

Mutations in ATLs are linked to human disease. Mutations in ATL3 are associated with hereditary sensory neuropathy (HSN),[16] and mutations in ATL1 are linked to HSN[17] and hereditary spastic paraplegia (HSP).[12] Research has identified a number of mutations that correspond to the disease phenotype, including the ATL3 Y192C[18] disease mutation that is equivalent to the Y196C mutation in ATL1.[6] Work to identify disease mutants remains ongoing, with a novel nonsense ATL3 mutation being identified in early 2023.[19] ATL3 HSN mutations affect the protein’s fusion cycle by causing aberrant tethering.[20] Similarly, an ATL1 HSP mutation was shown to increase tethering but not impact GTPase activity.[21]