PMID- 27203283
OWN - NLM
STAT- MEDLINE
DCOM- 20170406
LR  - 20240327
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 5
DP  - 2016
TI  - Disrupting Dimerization Translocates Soluble Epoxide Hydrolase to Peroxisomes.
PG  - e0152742
LID - 10.1371/journal.pone.0152742 [doi]
LID - e0152742
AB  - The epoxyeicosatrienoic acid (EET) neutralizing enzyme soluble epoxide hydrolase 
      (sEH) is a neuronal enzyme, which has been localized in both the cytosol and 
      peroxisomes. The molecular basis for its dual localization remains unclear as sEH 
      contains a functional peroxisomal targeting sequence (PTS). Recently, a missense 
      polymorphism was identified in human sEH (R287Q) that enhances its peroxisomal 
      localization. This same polymorphism has also been shown to generate weaker sEH 
      homo-dimers. Taken together, these observations suggest that dimerization may 
      mask the sEH PTS and prevent peroxisome translocation. In the current study, we 
      test the hypothesis that dimerization is a key regulator of sEH subcellular 
      localization. Specifically, we altered the dimerization state of sEH by 
      introducing substitutions in amino acids responsible for the dimer-stabilizing 
      salt-bridge. Green Fluorescent Protein (GFP) fusions of each of mutants were 
      co-transfected into mouse primary cultured cortical neurons together with a 
      PTS-linked red fluorescent protein to constitutively label peroxisomes. Labeled 
      neurons were analyzed using confocal microscopy and co-localization of sEH with 
      peroxisomes was quantified using Pearson's correlation coefficient. We find that 
      dimer-competent sEH constructs preferentially localize to the cytosol, whereas 
      constructs with weakened or disrupted dimerization were preferentially targeted 
      to peroxisomes. We conclude that the sEH dimerization status is a key regulator 
      of its peroxisomal localization.
FAU - Nelson, Jonathan W
AU  - Nelson JW
AD  - Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science 
      University, Portland, OR, 97239-3098, United States of America.
AD  - Department of Molecular and Medical Genetics, Oregon Health & Science University, 
      Portland, OR, 97239-3098, United States of America.
AD  - The Knight Cardiovascular Institute, Oregon Health & Science University, 
      Portland, OR, 97239-3098, United States of America.
FAU - Das, Anjali J
AU  - Das AJ
AD  - Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science 
      University, Portland, OR, 97239-3098, United States of America.
FAU - Barnes, Anthony P
AU  - Barnes AP
AD  - The Knight Cardiovascular Institute, Oregon Health & Science University, 
      Portland, OR, 97239-3098, United States of America.
AD  - Pape Family Research Center, Department of Pediatrics Oregon Health & Science 
      University, Portland, OR, 97239-3098, United States of America.
FAU - Alkayed, Nabil J
AU  - Alkayed NJ
AD  - Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science 
      University, Portland, OR, 97239-3098, United States of America.
AD  - The Knight Cardiovascular Institute, Oregon Health & Science University, 
      Portland, OR, 97239-3098, United States of America.
LA  - eng
GR  - R01 NS044313/NS/NINDS NIH HHS/United States
GR  - T32 HL094294/HL/NHLBI NIH HHS/United States
GR  - P30 NS061800/NS/NINDS NIH HHS/United States
GR  - R01 NS079433/NS/NINDS NIH HHS/United States
GR  - R01 NS070837/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20160520
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Dimerization
MH  - Epoxide Hydrolases/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neurons/metabolism
MH  - Peroxisomes/*metabolism
MH  - Protein Transport
MH  - Subcellular Fractions/enzymology
PMC - PMC4874748
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2016/05/21 06:00
MHDA- 2017/04/07 06:00
PMCR- 2016/05/20
CRDT- 2016/05/21 06:00
PHST- 2015/06/19 00:00 [received]
PHST- 2016/03/18 00:00 [accepted]
PHST- 2016/05/21 06:00 [entrez]
PHST- 2016/05/21 06:00 [pubmed]
PHST- 2017/04/07 06:00 [medline]
PHST- 2016/05/20 00:00 [pmc-release]
AID - PONE-D-15-26967 [pii]
AID - 10.1371/journal.pone.0152742 [doi]
PST - epublish
SO  - PLoS One. 2016 May 20;11(5):e0152742. doi: 10.1371/journal.pone.0152742. 
      eCollection 2016.