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PMID: 10359649 Published · ppublish English Comparative Study Journal Article Research Support, U.S. Gov't, P.H.S.

Protein modification during biological aging: selective tyrosine nitration of the SERCA2a isoform of the sarcoplasmic reticulum Ca2+-ATPase in skeletal muscle.

The Biochemical journal ·Vol. 340 ( Pt 3) ·1999-06-15 ·Pages 657-69

Viner RI, Ferrington DA, Williams TD, Bigelow DJ, Schöneich C

Abstract

The accumulation of covalently modified proteins is an important hallmark of biological aging, but relatively few studies have addressed the detailed molecular-chemical changes and processes responsible for the modification of specific protein targets. Recently, Narayanan et al. [Narayanan, Jones, Xu and Yu (1996) Am. J. Physiol. 271, C1032-C1040] reported that the effects of aging on skeletal-muscle function are muscle-specific, with a significant age-dependent change in ATP-supported Ca2+-uptake activity for slow-twitch but not for fast-twitch muscle. Here we have characterized in detail the age-dependent functional and chemical modifications of the rat skeletal-muscle sarcoplasmic-reticulum (SR) Ca2+-ATPase isoforms SERCA1 and SERCA2a from fast-twitch and slow-twitch muscle respectively. We find a significant age-dependent loss in the Ca2+-ATPase activity (26% relative to Ca2+-ATPase content) and Ca2+-uptake rate specifically in SR isolated from predominantly slow-twitch, but not from fast-twitch, muscles. Western immunoblotting and amino acid analysis demonstrate that, selectively, the SERCA2a isoform progressively accumulates a significant amount of nitrotyrosine with age (approximately 3.5+/-0. 7 mol/mol of SR Ca2+-ATPase). Both Ca2+-ATPase isoforms suffer an age-dependent loss of reduced cysteine which is, however, functionally insignificant. In vitro, the incubation of fast- and slow-twitch muscle SR with peroxynitrite (ONOO-) (but not NO/O2) results in the selective nitration only of the SERCA2a, suggesting that ONOO- may be the source of the nitrating agent in vivo. A correlation of the SR Ca2+-ATPase activity and covalent protein modifications in vitro and in vivo suggests that tyrosine nitration may affect the Ca2+-ATPase activity. By means of partial and complete proteolytic digestion of purified SERCA2a with trypsin or Staphylococcus aureus V8 protease, followed by Western-blot, amino acid and HPLC-electrospray-MS (ESI-MS) analysis, we localized a large part of the age-dependent tyrosine nitration to the sequence Tyr294-Tyr295 in the M4-M8 transmembrane domain of the SERCA2a, close to sites essential for Ca2+ translocation.

MeSH Terms
Aging/metabolism Amino Acid Sequence Animals Biological Transport Calcium/metabolism Calcium-Transporting ATPases/chemistry,metabolism Cysteine/metabolism Endopeptidases/metabolism Isoenzymes/chemistry,metabolism Muscle Fibers, Fast-Twitch/enzymology Muscle Fibers, Slow-Twitch/enzymology Nitrates/metabolism Nitric Oxide/metabolism Oxygen/metabolism Peptide Fragments/chemistry,metabolism Protein Processing, Post-Translational Rats Rats, Inbred F344 Sarcoplasmic Reticulum/enzymology,metabolism Sulfhydryl Compounds/metabolism Tyrosine/analogs & derivatives,analysis,metabolism
Chemicals
Isoenzymes Nitrates Peptide Fragments Sulfhydryl Compounds peroxynitric acid Nitric Oxide 3-nitrotyrosine Tyrosine Endopeptidases Calcium-Transporting ATPases Cysteine Oxygen Calcium
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Viner R I
Department of Pharmaceutical Chemistry, University of Kansas, Simons Building, 2095 Constant Avenue, Lawrence, KS 66047, USA.
Ferrington D A
Williams T D
Bigelow D J
Schöneich C
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
0264-6021
Published
1999-06-15
Pages
657-69
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1220296
Subset
IM
Grants
NIA NIH HHS · P01AG12993 · United States
External Links
PubMed source PMC Full Text View journal details
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