# ER Morphology in the Pathogenesis of Hereditary
## 3 ER Shaping Proteins
### Atlastin-1 (SPG3a)  
Human Atlastin-1 (ATL1) is a GTPase that, on the basis of its structural features, can be classified as a member of the dynamin family of large GTPases and was first identified as the protein encoded by _SPG3A_, the gene found mutated in the earliest onset form of AD-HSP [9]. Two additional proteins extensively related to Atlastin-1 were later discovered in the human genome and thus named Atlastin-2 (ATL2) and Atlastin-3 (ATL3). ATL3 has also been implicated in human disease as its mutation is responsible for hereditary sensory and autonomic neuropathy (HSAN) [35; 36]. Mammalian atlastins differ in tissue expression, with ATL1 being mainly expressed in the central nervous system (CNS) [9; 37] whereas ATL2 and ATL3 are more ubiquitously expressed [38]. These proteins share twotransmembrane helices in addition to the GTPase domain, suggesting that they all reside within cellular membranes [37]. Although the structural fingerprint of ATL1 unequivocally reveals an ability to hydrolyze GTP, the functional role of this GTPase activity within the cell remained unknown for some time. An early subcellular localization was misleading: ATL1 was shown to be a Golgi-resident protein [39], possibly with a very limited localization within ER membranes. This interpretation led to the initial hypothesis that ATL1 might be involved in ER-Golgi membrane trafficking [39], perhaps in membrane fusion events due to its topological similarities to the mitofusins, or in vesicle budding and fission because of its resemblance to dynamin. Interestingly, it was later established that ATL2 and ATL3 localized specifically to the ER [38]. The extraordinary homology among human atlastins, however, suggested that all three proteins would be targeted to the same membranes. A key confirmation of the actual subcellular localization of atlastins came from _Drosophila_ where a single atlastin ortholog was identified. Indeed, endogenous _Drosophila_ atlastin was found in vivo to localize primarily to the ER [40; 41] and definitive ER localization was finally determined also for ATL1, when it was shown to interact physically with the ER-specific protein Reticulon-4a and to play a role in ER shaping [42]. Nevertheless, the actual function of ATL1 remained unresolved since only a broad hypothesis was proposed, based largely on the analogy to other members of the dynamin family of GTPases, that ATL1 would promote either the fusion or fission of ER tubules [42]. The existence of one atlastin gene in _Drosophila_ helped elucidate its precise cellular function. In vivo approaches combined with the in vitro proof that fly atlastin is sufficient to catalyze lipid bilayer fusion when incorporated into synthetic lipid vesicles demonstrated that atlastin is the mediator of the homotypic fusion of ER membranes [40]. Although Drosophila atlastin remains to date the only atlastin, with the exception of the very distantly related yeast [43] and plant orthologs [44], capable of promoting membrane fusion in vitro, it is accepted by extension that also vertebrate atlastins possess this functional property in vivo. Atlastins consist of a GTPase (G) domain, a helix bundle (HB) domain, two closely spaced transmembrane segments (TM1 and TM2), and a \(C\)-terminal tail (CT) containing an amphipathic helix (AH) [45; 46; 47]. Structural studies of the cytosolic domains of ATL1 have produced some confounding results that have predictably led to conflicting models for the mechanism of atlastin-mediated membrane fusion [46; 47]. A plausible model that reconciles the available crystal structures begins with GTP binding to atlastin monomers. In the next step, the monomers form a dimer with the bound GTP molecules buried at the interface. GTP hydrolysis by the dimer drives the association of the two HBs, forming a tight dimer. Finally, Pi and GDP are released sequentially, causing the dissociation of the dimer into monomers.