The CXXC motif at the N terminus of an α‐helical peptide

Iqbalsyah, Teuku M.; Moutevelis, Efrosini; Warwicker, Jim; Errington, Neil; Doig, Andrew J.

doi:10.1110/ps.062271506

Cited by 41 publications

(45 citation statements)

References 28 publications

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“…Given that the two cysteines are adjacent to the TM helix (Fig. 1b) and in view of a recent study showing that a CxxC motif is found at the N termini of ␣ helices stabilizing ␣ helical structures, this juxtaposition is noteworthy (37). Assuming an intrachain disulfide is formed in each stalk region, one possibility is that the CD3␥ TM helix is stabilized and perhaps even extended as an elongated helix above the plane of the cell membrane.…”

Section: Discussionmentioning

confidence: 86%

Importance of the CD3γ Ectodomain Terminal β-Strand and Membrane Proximal Stalk in Thymic Development and Receptor Assembly

Touma

Sun

Clayton

et al. 2007

The Journal of Immunology

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CD3εγ and CD3εδ are noncovalent heterodimers; each consists of Ig-like extracellular domains associated side-to-side via paired terminal β-strands that are linked to individual subunit membrane proximal stalk segments. CD3ε, CD3γ, and CD3δ stalks contain the RxCxxCxE motif. To investigate the functional importance of a CD3 stalk and terminal β-strand, we created a CD3γ double mutant CD3γC82S/C85S and a CD3γ β-strand triple mutant CD3γQ76S/Y78A/Y79A for use in retroviral transduction of lymphoid progenitors for comparison with CD3γwt. Although both mutant CD3γ molecules reduced association with CD3ε in CD3εγ heterodimers, CD3γQ76S/Y78A/Y79A abrogated surface TCR expression whereas CD3γC82S/C85S did not. Furthermore, CD3γC82S/C85S rescued thymic development in CD3γ−/− fetal thymic organ culture. However, the numbers of double-positive and single-positive thymocytes after CD3γC82S/C85S transduction were significantly reduced despite surface pre-TCR and TCR expression comparable to that of CD3γ−/− thymocytes transduced in fetal thymic organ culture with a retrovirus harboring CD3γwt cDNA. Furthermore, double-negative thymocyte development was perturbed with attenuated double-negative 3/double-negative 4 maturation and altered surface-expressed CD3εγ, as evidenced by the loss of reactivity with CD3γ N terminus-specific antisera. Single histidine substitution of either CD3γ stalk cysteine failed to restore CD3εγ association and conformation in transient COS-7 cell transfection studies. Thus, CD3γC82 and CD3γC85 residues likely are either reduced or form a tight intrachain disulfide loop rather than contribute to a metal coordination site in conjunction with CD3εC80 and CD3εC83. The implications of these results for CD3εγ and TCR structure and signaling function are discussed.

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Section: Discussionmentioning

confidence: 86%

Importance of the CD3γ Ectodomain Terminal β-Strand and Membrane Proximal Stalk in Thymic Development and Receptor Assembly

Touma

Sun

Clayton

et al. 2007

The Journal of Immunology

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“…Others have suggested the helix dipole (Hol et al 1978;Hol 1985;Iqbalsyah et al 2006), interaction with histidine (Polgar 1974;Lo Bello et al 1993), or ion pair formation (Griffiths et al 2002) as important features in cysteine reactivity. Integration of profiling with electrostatic analysis across the entire modifiable protein set allows us to comment generally on these observations and to identify possible mechanistic determinants for cysteine deprotonation.…”

Section: Discussionmentioning

confidence: 99%

Functional site profiling and electrostatic analysis of cysteines modifiable to cysteine sulfenic acid

et al. 2008

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Cysteine sulfenic acid (Cys-SOH), a reversible modification, is a catalytic intermediate at enzyme active sites, a sensor for oxidative stress, a regulator of some transcription factors, and a redox-signaling intermediate. This post-translational modification is not random: specific features near the cysteine control its reactivity. To identify features responsible for the propensity of cysteines to be modified to sulfenic acid, a list of 47 proteins (containing 49 known Cys-SOH sites) was compiled. Modifiable cysteines are found in proteins from most structural classes and many functional classes, but have no propensity for any one type of protein secondary structure. To identify features affecting cysteine reactivity, these sites were analyzed using both functional site profiling and electrostatic analysis. Overall, the solvent exposure of modifiable cysteines is not different from the average cysteine. The combined sequence, structure, and electrostatic approaches reveal mechanistic determinants not obvious from overall sequence comparison, including: (1) pK a s of some modifiable cysteines are affected by backbone features only; (2) charged residues are underrepresented in the structure near modifiable sites; (3) threonine and other polar residues can exert a large influence on the cysteine pK a ; and (4) hydrogen bonding patterns are suggested to be important. This compilation of Cys-SOH modification sites and their features provides a quantitative assessment of previous observations and a basis for further analysis and prediction of these sites. Agreement with known experimental data indicates the utility of this combined approach for identifying mechanistic determinants at protein functional sites.Keywords: functional site profile; redox signaling; cysteine sulfenic acid; cysteine reactivity; mechanistic determinants; post-translational modification; oxidative modification Supplemental material: see www.proteinscience.org Protein post-translational modifications are well known to play important biological roles by rapidly modifying the structure and function of proteins. The most common and well-known example is the involvement of protein phosphorylation in signal transduction. Analysis of phosphorylation sites has led to a better understanding of kinase substrate specificity (Brinkworth et al. 2002;Kobe et al. 2005), methods for site prediction (Koenig and Grabe 2004;Huang et al. 2005;Plewczynski et al. 2005;Xue et al. 2005), and a combined experimental/computational approach that has led to a better understanding of the yeast phosphoproteome (Brinkworth et al. 2006;Molina et al. 2007).The reversible oxidation of cysteine side chains to cysteine sulfenic acid (Cys-SOH) has been recognized as Reprint requests to: Jacquelyn S. Fetrow, 100 Olin Physical Laboratory, 7507 Reynolda Station, Wake Forest University, Winston-Salem, NC 27019-7507, USA; e-mail: fetrowjs@wfu.edu; fax: (336) 758-6142.Abbreviations: Prx, peroxiredoxin; Msr, methionine sulfoxide reductase; Cys-SOH, cysteine sulfenic acid; GAPDH...

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“…Therefore, these two catalytic cysteines are presumably located near the adenylated form of U8. Second, Cys 265 and Cys 268 are at the N terminus of an ␣-helix, which is a conserved location of a CXXC motif in the thiol:disulfide oxidoreductase superfamily (60). In this superfamily, the CXXC motif is essential for the catalysis of redox reactions involving formation of reversible intramolecular disulfide bonds.…”

Section: Proposed Model Of S 4 U Formation In M Maripaludis-mentioning

confidence: 99%

Biosynthesis of 4-Thiouridine in tRNA in the Methanogenic Archaeon Methanococcus maripaludis

Liu

Zhu

Nakamura

et al. 2012

Journal of Biological Chemistry

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Background: Bacterial ThiI catalyzes 4-thiouridine biosynthesis by using a rhodanese-like domain for sulfur transfer. Results: ThiI in methanogenic archaea employs a conserved CXXC motif to generate persulfide and disulfide intermediates for sulfur transfer. Conclusion: Methanogens possess a unique sulfur relay strategy. Significance: Sulfur metabolism in methanogens is a model for the evolution of sulfur metabolism in the anaerobic sulfide-rich environments common on ancient earth.

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The CXXC motif at the N terminus of an α‐helical peptide

Cited by 41 publications

References 28 publications

Importance of the CD3γ Ectodomain Terminal β-Strand and Membrane Proximal Stalk in Thymic Development and Receptor Assembly

Importance of the CD3γ Ectodomain Terminal β-Strand and Membrane Proximal Stalk in Thymic Development and Receptor Assembly

Functional site profiling and electrostatic analysis of cysteines modifiable to cysteine sulfenic acid

Biosynthesis of 4-Thiouridine in tRNA in the Methanogenic Archaeon Methanococcus maripaludis

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