Redox active motifs in selenoproteins.
Selenoproteins use the rare amino acid selenocysteine (Sec) to act as the first line of defense against oxidants, which are linked to aging, cancer, and neurodegenerative diseases. Many selenoproteins are oxidoreductases in which the reactive Sec is connected to a neighboring Cys and able to form a ring. These Sec-containing redox motifs govern much of the reactivity of selenoproteins. To study their fundamental properties, we have used (77)Se NMR spectroscopy in concert with theoretical calculations to determine the conformational preferences and mobility of representative motifs. This use of (77)Se as a probe enables the direct recording of the properties of Sec as its environment is systematically changed. We find that all motifs have several ring conformations in their oxidized state. These ring structures are most likely stabilized by weak, nonbonding interactions between the selenium and the amide carbon. To examine how the presence of selenium and ring geometric strain governs the motifs' reactivity, we measured the redox potentials of Sec-containing motifs and their corresponding Cys-only variants. The comparisons reveal that for C-terminal motifs the redox potentials increased between 20-25 mV when the selenenylsulfide bond was changed to a disulfide bond. Changes of similar magnitude arose when we varied ring size or the motifs' flanking residues. This suggests that the presence of Sec is not tied to unusually low redox potentials. The unique roles of selenoproteins in human health and their chemical reactivities may therefore not necessarily be explained by lower redox potentials, as has often been claimed.
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716;
Fei
F
Li
Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529; and.
Patricia B
PB
Lutz
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716;
Yuliya
Y
Pepelyayeva
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Elias S J
ES
Arnér
Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529; and rozovsky@udel.edu CBayse@odu.edu.
Craig A
CA
Bayse
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716; rozovsky@udel.edu CBayse@odu.edu.
Sharon
S
Rozovsky
D000818:Animals; D001483:Base Sequence; D020134:Catalytic Domain; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D017434:Protein Structure, Tertiary; D012643:Selenium / Q000737:chemistry / Q000378:metabolism*; D017279:Selenocysteine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051140:Selenoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013440:Sulfides / Q000737:chemistry / Q000378:metabolism; D013455:Sulfur / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
D051140:Selenoproteins; D013440:Sulfides; D017279:Selenocysteine; D013455:Sulfur; D012643:Selenium