Protein Targeting

Targeting of Tail-Anchored Proteins

Targeting by tail-anchor sequences occurs by two different mechanisms.  
The blue protein is targeted by a receptor mediated ATP dependent mechanism.  The green protein is targeted by a conformational change that occurs in the cytoplasm.

Tail-anchors are hydrophobic sequences located at the carboxyl-terminus of a variety of functionally unrelated protein.  These sequences serve to target the protein to the appropriate subcellular membrane as well as to anchor it into the lipid bilayer 

A) Receptor mediated, ATP dependent, targeting.  This pathway is used by Vamp proteins, Sec61b and g, and several proteins targeted initially to the endoplasmic reticulum and that are then sorted throughout the secretory pathway.

B) Spontaneous insertion does not require ATP. Bcl-2 family proteins, cytochrome b5 and Acta are all targeted by a mechanism that involves an equilibrium in the cytoplasm that competes with membrane assembly.  At least in the case of Bax it appears that the equilibrium in the cytoplasm is between insertion competent and insertion blocked conformations. Etoposide leads the cell to trigger a conformational change in Bax that causes it to insert into mitochondria and ER early during apoptosis.(Kim PK et al Biochemistry. 1997)

Because they are so close to the carboxyl-terminus the tail-anchor is still inside the ribosome when translation of the protein finishes. Therefore, these proteins must be targeted to membranes post-translationally. There are two known mechanisms for targeting these protein (A and B above).