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First published online 13 May 2008
doi: 10.1242/jcs.012013

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Identification of a novel N-terminal hydrophobic sequence that targets proteins to lipid droplets

Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039, USA

^* Author for correspondence (e-mail: richard.anderson{at}utsouthwestern.edu)

Accepted 11 March 2008

AAM-B is a putative methyltransferase that is a resident protein of lipid droplets. We have identified an N-terminal 28 amino acid hydrophobic sequence that is necessary and sufficient for targeting the protein to droplets. This sequence will also insert AAM-B into the endoplasmic reticulum (ER). A similar hydrophobic sequence (1-23) in the cytochrome p450 2C9 cannot substitute for 1-28 and only inserts AAM-B into the ER, which indicates that hydrophobicity and ER anchoring are not sufficient to reach the droplet. We found that a similar N-terminal hydrophobic sequence in cytochrome b5 reductase 3 and ALDI could also heterologously target proteins to droplets. Targeting is not affected by changing a conserved proline residue that potentially facilitates the formation of a hairpin loop to leucine. By contrast, targeting is blocked when AAM-B amino acids 59-64 or 65-70, situated downstream of the hydrophobic sequence, are changed to alanines. AAM-B-GFP expressed in Saccharomyces cerevisiae is also faithfully targeted to lipid bodies, indicating that the targeting mechanism is evolutionarily conserved. In conclusion, a class of hydrophobic sequences exists that when placed at the N-terminus of a protein will cause it to accumulate in droplets and in the ER.

Key words: Organelle targeting, ER, Lipid droplet, Adiposome, Membrane traffic