Eukaryotic proteins of the reticulon (RTN) family all share an association with the endoplasmic reticulum (ER). Whereas amino-terminal regions are not related to one another, all reticulon proteins share a 200 amino acid residue region of sequence similarity at the C-terminal. This region contains two large hydrophobic regions separated by a 66 residue hydrophilic segment. The conserved hydrophobic C-terminal portion has been shown to play an essential role in the association of reticulons with the ER membrane. The hydrophobic portions are supposed to be membrane-embedded and the hydrophilic 66 residue localized to the lumenal/extracellular face of the membrane. Most reticulons have a di-lysine ER retention motif at the C-terminal. Because of their likely association with the rough as well as the smooth ER, the reticulons might play some role in transport processes or in regulation of intracellular calcium levels. It has been suggested that the reticulons may be serving as ER-associated channel-like complexes [PMID:7844160, PMID:8833145, PMID:9693037, PMID:10667797].