RGD Reference Report - Mitochondrial targeting of cytochrome P450 proteins containing NH2-terminal chimeric signals involves an unusual TOM20/TOM22 bypass mechanism. - Rat Genome Database

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Mitochondrial targeting of cytochrome P450 proteins containing NH2-terminal chimeric signals involves an unusual TOM20/TOM22 bypass mechanism.

Authors: Anandatheerthavarada, Hindupur K  Sepuri, Naresh Babu V  Avadhani, Narayan G 
Citation: Anandatheerthavarada HK, etal., J Biol Chem. 2009 Jun 19;284(25):17352-63. doi: 10.1074/jbc.M109.007492. Epub 2009 Apr 28.
RGD ID: 13838795
Pubmed: PMID:19401463   (View Abstract at PubMed)
PMCID: PMC2719370   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M109.007492   (Journal Full-text)

Previously we showed that xenobiotic inducible cytochrome P450 (CYP) proteins are bimodally targeted to the endoplasmic reticulum and mitochondria. In this study, we investigated the mechanism of delivery of chimeric signal containing CYP proteins to the peripheral and channel-forming mitochondrial outer membrane translocases (TOMs). CYP+33/1A1 and CYP2B1 did not require peripheral TOM70, TOM20, or TOM22 for translocation through the channel-forming TOM40 protein. In contrast, CYP+5/1A1 and CYP2E1 were able to bypass TOM20 and TOM22 but required TOM70. CYP27, which contains a canonical cleavable mitochondrial signal, required all of the peripheral TOMs for its mitochondrial translocation. We investigated the underlying mechanisms of bypass of peripheral TOMs by CYPs with chimeric signals. The results suggested that interaction of CYPs with Hsp70, a cytosolic chaperone involved in the mitochondrial import, alone was sufficient for the recognition of chimeric signals by peripheral TOMs. However, sequential interaction of chimeric signal containing CYPs with Hsp70 and Hsp90 resulted in the bypass of peripheral TOMs, whereas CYP27A1 interacted only with Hsp70 and was not able to bypass peripheral TOMs. Our results also show that delivery of a chimeric signal containing client protein by Hsp90 required the cytosol-exposed NH(2)-terminal 143 amino acids of TOM40. TOM40 devoid of this domain was unable to import CYP proteins. These results suggest that compared with the unimodal mitochondrial targeting signals, the chimeric mitochondrial targeting signals are highly evolved and dynamic in nature.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Tomm20Ratprotein targeting to mitochondrion involved_inIMP PMID:19401463UniProt 
Tomm22Ratprotein targeting to mitochondrion involved_inIMP PMID:19401463UniProt 
Tomm40Ratprotein targeting to mitochondrion involved_inIMP PMID:19401463UniProt 
Tomm70Ratprotein targeting to mitochondrion involved_inIMP PMID:19401463UniProt 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Cyp2e1Ratendoplasmic reticulum membrane located_inIDA PMID:19401463UniProt 
Cyp1a1Ratmitochondrial inner membrane located_inIDA PMID:19401463UniProt 
Cyp27a1Ratmitochondrial inner membrane located_inIDA PMID:19401463UniProt 
Cyp2b1Ratmitochondrial inner membrane located_inIDA PMID:19401463UniProt 
Cyp2e1Ratmitochondrial inner membrane located_inIDA PMID:19401463UniProt 

Molecular Function

  

Objects Annotated

Genes (Rattus norvegicus)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Cyp27a1  (cytochrome P450, family 27, subfamily a, polypeptide 1)
Cyp2b1  (cytochrome P450, family 2, subfamily b, polypeptide 1)
Cyp2e1  (cytochrome P450, family 2, subfamily e, polypeptide 1)
Tomm20  (translocase of outer mitochondrial membrane 20)
Tomm22  (translocase of outer mitochondrial membrane 22)
Tomm40  (translocase of outer mitochondrial membrane 40)
Tomm70  (translocase of outer mitochondrial membrane 70)


Additional Information