FIGURE 2.

HSP-related proteins regulate ER morphology through HP domains. HSP is an axonopathy that is caused by mutation of various genes and which is characterized by the degeneration of motor neurons in the corticospinal tract and consequent progressive spasticity and weakness of the lower limbs. The proteins encoded by such HSP-related genes—including spastin, REEPs, atlastins, and reticulons as well as protrudin—contain an HP domain. This hydrophobic wedge-shaped domain inserts into the cytosolic side of the ER membrane, resulting in bending of the membrane bilayer and the formation of high-curvature tubules. The HSP-associated mutant forms of these proteins give rise to structural defects in the smooth ER and an abnormal ER network.