Influence of protein-protein interactions on the cellular localization of cytochrome P450.
BACKGROUND
Microsomal CYPs are integral membrane proteins that are localized in the endoplasmic reticulum (ER), which is critical for their function. CYPs are co-translationally inserted into the rough ER membrane and are then either directly retained in the smooth ER or retained by a retrieval mechanism or targeted for ER-associated degradation. Protein-protein interactions are likely to be important for proper cellular targeting of CYPs.


OBJECTIVE
Progress in understanding the mechanisms of cellular targeting and ER retention of CYPs is reviewed with emphasis on the role of protein-protein interactions. Possible mechanisms of direct retention are the incorporation of CYPs into an immobile complex in the ER membrane, homooligomerization that prevents inclusion in transport vesicles, exclusion of CYP monomers from transport vesicles or targeting of CYPs to an ER subdomain away from sites of transport vesicle formation. Degradation of CYPs occurs either by lysosomal mechanisms or by the ubiquitin-proteasomal pathway.


METHODS
The scope of this review includes studies published in the research literature that have defined the targeting of CYPs to the ER, the retention of CYPs in the ER and the degradation of CYPs.


CONCLUSIONS
Targeting of CYPs to the ER is well understood and involves signal recognition particle-mediated delivery to the sec61 complex. The mechanism of ER retention of CYPs remains unclear, but self-oligomerization or binding to large immobile networks do not underlie ER retention of CYPs. An ER retention 'receptor' remains elusive, but BAP31 is important for the proper cellular localization of CYPs and Dap1p is a CYP-binding protein that is a candidate for such a receptor. Identification of protein binding partners of CYPs will be critical to understanding the mechanism of ER retention.
Szczesna-Skorupa
Elzbieta
E
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Kemper
Byron
B
D001692:Biological Transport; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*
D011506:Proteins; D003577:Cytochrome P-450 Enzyme System