PMID- 10339593
OWN - NLM
STAT- MEDLINE
DCOM- 19990624
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 11
DP  - 1999 May 25
TI  - Microtubule dysfunction by posttranslational nitrotyrosination of alpha-tubulin: 
      a nitric oxide-dependent mechanism of cellular injury.
PG  - 6365-70
AB  - NO2Tyr (3-Nitrotyrosine) is a modified amino acid that is formed by nitric
      oxide-derived species and has been implicated in the pathology of diverse human
      diseases. Nitration of active-site tyrosine residues is known to compromise
      protein structure and function. Although free NO2Tyr is produced in abundant
      concentrations under pathological conditions, its capacity to alter protein
      structure and function at the translational or posttranslational level is
      unknown. Here, we report that free NO2Tyr is transported into mammalian cells and
      selectively incorporated into the extreme carboxyl terminus of alpha-tubulin via 
      a posttranslational mechanism catalyzed by the enzyme tubulin-tyrosine ligase. In
      contrast to the enzymatically regulated carboxyl-terminal
      tyrosination/detyrosination cycle of alpha-tubulin, incorporation of NO2Tyr shows
      apparent irreversibility. Nitrotyrosination of alpha-tubulin induces alterations 
      in cell morphology, changes in microtubule organization, loss of
      epithelial-barrier function, and intracellular redistribution of the motor
      protein cytoplasmic dynein. These observations imply that posttranslational
      nitrotyrosination of alpha-tubulin invokes conformational changes, either
      directly or via allosteric interactions, in the surface-exposed carboxyl terminus
      of alpha-tubulin that compromises the function of this critical domain in
      regulating microtubule organization and binding of motor- and
      microtubule-associated proteins. Collectively, these observations illustrate a
      mechanism whereby free NO2Tyr can impact deleteriously on cell function under
      pathological conditions encompassing reactive nitrogen species production. The
      data also yield further insight into the role that the alpha-tubulin
      tyrosination/detyrosination cycle plays in microtubule function.
FAU - Eiserich, J P
AU  - Eiserich JP
AD  - Department of Anesthesiology and Center for Free Radical Biology, University of
      Alabama, Birmingham, AL 35233, USA. jason.eiserich@ccc.uab.edu
FAU - Estevez, A G
AU  - Estevez AG
FAU - Bamberg, T V
AU  - Bamberg TV
FAU - Ye, Y Z
AU  - Ye YZ
FAU - Chumley, P H
AU  - Chumley PH
FAU - Beckman, J S
AU  - Beckman JS
FAU - Freeman, B A
AU  - Freeman BA
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Tubulin)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 3604-79-3 (3-nitrotyrosine)
RN  - 42HK56048U (Tyrosine)
RN  - EC 3.6.4.2 (Dyneins)
RN  - EC 6.3.2.- (Peptide Synthases)
RN  - EC 6.3.2.- (tyrosyltubulin ligase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Binding Sites
MH  - Cell Membrane Permeability
MH  - Dyneins/metabolism
MH  - Humans
MH  - Microtubules/*physiology/*ultrastructure
MH  - Nitric Oxide/*metabolism
MH  - Peptide Synthases/*metabolism
MH  - *Protein Processing, Post-Translational
MH  - Tubulin/chemistry/*metabolism
MH  - Tumor Cells, Cultured
MH  - Tyrosine/*analogs & derivatives/metabolism
PMC - PMC26887
EDAT- 1999/05/26 00:00
MHDA- 1999/05/26 00:01
CRDT- 1999/05/26 00:00
PHST- 1999/05/26 00:00 [pubmed]
PHST- 1999/05/26 00:01 [medline]
PHST- 1999/05/26 00:00 [entrez]
AID - 10.1073/pnas.96.11.6365 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 May 25;96(11):6365-70. doi:
      10.1073/pnas.96.11.6365.