Reticulons (RTNs in vertebrates and reticulon-like proteins or RNTls in other eukaryotes) are a group of evolutionary conservative proteins residing predominantly in endoplasmic reticulum, primarily playing a role in promoting membrane curvature. In addition, reticulons may play a role in nuclear pore complex formation, vesicle formation, and other processes yet to be defined. They have also been linked to oligodendrocyte roles in inhibition of neurite outgrowth. Some studies link RTNs with Alzheimer's disease and amyotrophic lateral sclerosis. All eukaryotes studied so far carry RTN genes in their genomes. The reticulons are absent only in archaea and bacteria. Mammals have four reticulon genes, RTN1, RTN2, RTN3, RTN4. Plants possess a greater number of reticulon isoforms, with 21 having been identified in the commonly used model organism Arabidopsis thaliana. The genes possess a number of exons and introns and are accordingly spliced into many isoforms. C-terminal region of RTNs contains a highly conservative reticulon homology domain (RHD) while other parts of the protein may vary even within a single organism. A peculiar feature of RTN4's isoform RTN4A (Nogo-A) is its ability to inhibit axonal growth. This reticulon subform is absent in fish, a taxon known for the heightened ability of its CNS to regenerate after injury. Transmembrane 33 (TMEM33) exogenously suppresses reticulon 4C function and therefore may play a role in dictating membrane curvature through inhibition of reticulon function.
Structure
Evolutionary history Reticulon proteins, which range from 200-1,200 amino acids, have been tracked in all eukaryotic organisms that have been examined. The family of vertebrate proteins are called reticulons, and all other located eukaryotes are called reticulon-like proteins. Some examples of explored reticulon genomes of eukaryotes are in Homo sapiens, Mus musculus, Danio rerio, Drosophila melanogaster, Arabidopsis thaliana, and Saccharomyces cerevisiae. These genomes are not found in either archaea or bacteria. Because of their absence from prokaryotes and close association with the endoplasmic reticulum (ER), it is proposed that reticulons have evolved with the eukaryotic endomembrane system. In mammals, there are four reticulon genes: RTN1-4. RTN 3 and 4 have sequence identity more closely related at 73% than between 2 and 4 with only a 52% sequence identity. There is a divergence in sequence between reticulons as their splice isoforms can be variable, even in the same organism. This is consistent with the evolution of species and cell-specific roles for reticulons. The longest isoform, Nogo-A, has shown through studies that it can inhibit neurite outgrowth and regeneration. However, this isoform is absent in fish where regeneration of central nervous system is extensive. Reticulons can vary in function between species.
Reticulon protein structure The reticulon family contain a carboxy-terminal reticulon homology domain (RHD) that has two hydrophobic regions of 28-36 amino acids. Those regions are supposedly embedded in the membrane. Those regions are separated by the 60-70 amino acids of the hydrophilic loop. Following the loop is a carboxy-terminal tail which has a length of about 50 amino acids. The amino-terminal domains are not similar to reticulons within the family. However, the three-dimensional structure has been preserved from yeasts to plants to humans. The hydrophobic region of the structure is abnormally long compared to other transmembrane domains. The structure of the reticulon may be related to the function of this protein.
Localization in ER, N- and C-terminal ends Reticulons are typically in the ER of cells; however, they have additionally been found on cell surfaces in mammals and on the surface of oligodendrocytes where they inhibit axon growth. The N-terminal, loop region and C-terminal are all on the cytosol side of the ER membrane and they are able to interact with other cytosolic proteins. N-terminal regions in reticulon proteins are diversified in interacting with other substrates. Overall, three models have been identified of RHD topology. One finding suggests that the amino-acid terminus and the 66-loop extend into the extracellular space. This would indicate that the hydrophobic region double-backs on itself in the membrane. Other data suggests that the amino-terminal is intracellular. Lastly, a third model explains the 66-loop and amino-terminal domain are cytoplasmic. All of these models suggest that reticulons may have different topologies at different regions such as the ER and plasma membrane. This would allow them to not only look different at each location, but be able to carry different roles in the cell and in different cell types. The first reticulon protein RTN1 was characterized as an antigen for neuroendocrine cells from a cDNA in neural tissue. It was later renamed when it was proved to be associated with the ER from several different methods. Reticulons do not have an ER localization sequence, but the RHD hydrophobic region is able to target protein-RTN to the ER by green fluorescence. Without the RHD, there is no association with the ER. Reticulons have localized to the ER in the following organisms: yeast, Arabidopsis, Xenopus, Drosophila and mammals.
Function
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