Question

You are trying to treat the following diseases using gene therapy. Using your knowledge, what targeting sequences would the engineered genes need in order to get the protein to the correct final destination? B Achondrogenesis (GMAP-210)

i know this genetic disease involves a mutation with trip2 gene which plays a key role in the function and structure of the Golgi apparatus, and i think this gene uses ERSS as well as possibly using KDEL but I'm not sure on how to tie this all together and I'm not sure if I'm on the right track. Please help

Answer 1

B. Achondrogenesis are serious disorders that affect bone and cartilage development. Achondrogenesis is caused by loss of Trip 11 gene that encodes for Golgi microtubule-associated protein 210 (GMAP-210). GMAP0210 maintains the structure of Golgi. In order for the protein to be targeted to Golgi, it should be synthesized on the ribosomes linked to endoplasmic reticulum. Hence, there should be a N terminal signal peptide that binds to signal recognition peptide for transport to ER lumen. However, there should be no KDEL sequence as it will retrieve the protein to ER from Golgi if accidentally transported. Otherwise it will be retained in ER. It should have also lack KKXX sequence in the C terminus, as this sequence causes the protein to reenter the ER from Golgi.

A sequence F/L-L/I/V-X-X-R/K, in which X is any amino acid, is been shown to be important for yeast Golgi protein insertion. KXD/E has been identified as a Golgi retention signal, which is a COPI interaction motif. It should also lack transmembrane domains, and start and stop sequences, for membrane insertion. Other Golgi retrieval signal includes domain rich is arginine or lysine. Thus, for retention of the GMAP-210 in Golgi, it should have N-terminal signal peptide sequence (ERSS) and Golgi retrieval signal like KXD/E or F/L-L/I/V-X-X-R/K.