Identification of Short Amino Acid Sequences That Correlate with Cytoplasmic Retention of Human Proteins

One group of human proteins found in the cytoplasm, but not in the nucleus, is characterized by the presence of short (6-9 aa), specific amino acid sequences thought to be involved in retaining proteins in the cytoplasm (cytoplasmic retention sequences). While strong evidence supports the ability of some peptides to act in this way, the number of such supported cases is small. We have taken the view that the situation would be improved by enhancing the methods available to identify cytoplasmic retention (CR) sequences. Here, we describe an appropriate bioinformatic method to identify CR peptides using information about their location at the ends of cytoplasmic proteins. The method was then used to link seven different human cytoplasmic proteins with sequences suggested to have cytoplasmic retention activity. Further bioinformatic analysis was carried out with isoforms of the cytoplasmic proteins identified. Amino acid sequence information showed that while the proposed CR amino acid sequences can be the same or distinct in different protein isoforms, they are always located at the same site in the protein. For instance, while the proposed retention sequence of CCDC57 isoform X18 is MLARLVSNS, in isoform 7 it is SEPALNEL, yet the two sequences are each located between amino acids 5 and 13 in the CCDC57 sequence. The results support the view that the protein isoform is involved in determining the location of the CR sequence in a protein, while the amino acid sequence itself affects other variables such as the sub-region of the cytoplasm the protein needs to occupy. Overall, the study yielded identification of 15 candidate CR peptides in which 10 of the 15 have unrelated amino acid sequences.