Cysteines and Disulfide Bonds As Structure-Forming Units: Insights From Different Domains of Life and the Potential for Characterization by NMR

Overview

Journal Front Chem

Specialty Chemistry

Date 2020 May 12

PMID 32391319

Citations 55

Authors

Christoph Wiedemann

Amit Kumar

Andras Lang

Oliver Ohlenschlager

Affiliations

Soon will be listed here.

Abstract

Disulfide bridges establish a fundamental element in the molecular architecture of proteins and peptides which are involved e.g., in basic biological processes or acting as toxins. NMR spectroscopy is one method to characterize the structure of bioactive compounds including cystine-containing molecules. Although the disulfide bridge itself is invisible in NMR, constraints obtained via the neighboring NMR-active nuclei allow to define the underlying conformation and thereby to resolve their functional background. In this mini-review we present shortly the impact of cysteine and disulfide bonds in the proteasome from different domains of life and give a condensed overview of recent NMR applications for the characterization of disulfide-bond containing biomolecules including advantages and limitations of the different approaches.

Citing Articles

Using AlphaFold2 to Predict the Conformations of Side Chains in Folded Proteins.

Maisuradze G, Thakur A, Khatri K, Haldane A, Levy R bioRxiv. 2025; .

PMID: 39990457 PMC: 11844428. DOI: 10.1101/2025.02.10.637534.

High-Performance Structures of Biopolymer Gels Activated with Scleroprotein Crosslinkers.

Prochon M, Dzeikala O, Szczepanik S Molecules. 2025; 30(3).

PMID: 39942731 PMC: 11820096. DOI: 10.3390/molecules30030627.

Cysteine-Directed Isobaric Labeling Combined with GeLC-FAIMS-MS for Quantitative Top-Down Proteomics.

Matzanke T, Kaulich P, Jeong K, Takemori A, Takemori N, Kohlbacher O J Proteome Res. 2025; 24(3):1470-1480.

PMID: 39885717 PMC: 11894657. DOI: 10.1021/acs.jproteome.4c00835.

Noncanonical inhibition of topoisomerase II alpha by oxidative stress metabolites.

Flor A, Wolfgeher D, Kron S Redox Biol. 2025; 80:103504.

PMID: 39879737 PMC: 11810846. DOI: 10.1016/j.redox.2025.103504.

A functional helix shuffled variant of the B domain of Staphylococcus aureus.

Bobolowski H, Fiedler E, Haupts U, Lilie H, Weininger U Protein Sci. 2025; 34(2):e70012.

PMID: 39840789 PMC: 11751873. DOI: 10.1002/pro.70012.

References

van de Locht A, Lamba D, Bauer M, Huber R, Friedrich T, Kroger B . Two heads are better than one: crystal structure of the insect derived double domain Kazal inhibitor rhodniin in complex with thrombin. EMBO J. 1995; 14(21):5149-57. PMC: 394622. DOI: 10.1002/j.1460-2075.1995.tb00199.x. View

Denisov S, Ippel J, Mans B, Dijkgraaf I, Hackeng T . SecScan: a general approach for mapping disulfide bonds in synthetic and recombinant peptides and proteins. Chem Commun (Camb). 2018; 55(10):1374-1377. DOI: 10.1039/c8cc08777f. View

Martin O, Villegas M, Vila J, Scheraga H . Analysis of 13Calpha and 13Cbeta chemical shifts of cysteine and cystine residues in proteins: a quantum chemical approach. J Biomol NMR. 2010; 46(3):217-25. PMC: 2864455. DOI: 10.1007/s10858-010-9396-x. View

Armstrong D, Kaas Q, Rosengren K . Prediction of disulfide dihedral angles using chemical shifts. Chem Sci. 2018; 9(31):6548-6556. PMC: 6115640. DOI: 10.1039/c8sc01423j. View

Cohen I, Coban M, Shahar A, Sankaran B, Hockla A, Lacham S . Disulfide engineering of human Kunitz-type serine protease inhibitors enhances proteolytic stability and target affinity toward mesotrypsin. J Biol Chem. 2019; 294(13):5105-5120. PMC: 6442025. DOI: 10.1074/jbc.RA118.007292. View

Christinger H, Fuh G, de Vos A, Wiesmann C . The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1. J Biol Chem. 2003; 279(11):10382-8. DOI: 10.1074/jbc.M313237200. View

Zhang J . Protein-length distributions for the three domains of life. Trends Genet. 2000; 16(3):107-9. DOI: 10.1016/s0168-9525(99)01922-8. View

Ramanujam V, Shen Y, Ying J, Mobli M . Residual Dipolar Couplings for Resolving Cysteine Bridges in Disulfide-Rich Peptides. Front Chem. 2020; 7:889. PMC: 6987419. DOI: 10.3389/fchem.2019.00889. View

Brocchieri L, Karlin S . Protein length in eukaryotic and prokaryotic proteomes. Nucleic Acids Res. 2005; 33(10):3390-400. PMC: 1150220. DOI: 10.1093/nar/gki615. View

10.

Mills J, Whitford P, Shaffer J, Onuchic J, Adams J, Jennings P . A novel disulfide bond in the SH2 Domain of the C-terminal Src kinase controls catalytic activity. J Mol Biol. 2006; 365(5):1460-8. PMC: 2741090. DOI: 10.1016/j.jmb.2006.10.076. View

11.

Lee E, Lee D . Emerging roles of protein disulfide isomerase in cancer. BMB Rep. 2017; 50(8):401-410. PMC: 5595169. DOI: 10.5483/bmbrep.2017.50.8.107. View

12.

Chhabra S, Belgi A, Bartels P, van Lierop B, Robinson S, Kompella S . Dicarba analogues of α-conotoxin RgIA. Structure, stability, and activity at potential pain targets. J Med Chem. 2014; 57(23):9933-44. DOI: 10.1021/jm501126u. View

13.

Nielsen L, Foged M, Albert A, Bertelsen A, Soltoft C, Robinson S . The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework. J Biol Chem. 2019; 294(22):8745-8759. PMC: 6552430. DOI: 10.1074/jbc.RA119.007491. View

14.

Schlott B, Wohnert J, Icke C, Hartmann M, Ramachandran R, Guhrs K . Interaction of Kazal-type inhibitor domains with serine proteinases: biochemical and structural studies. J Mol Biol. 2002; 318(2):533-46. DOI: 10.1016/S0022-2836(02)00014-1. View

15.

de Oliveira Dias R, Franco O . Cysteine-stabilized αβ defensins: From a common fold to antibacterial activity. Peptides. 2015; 72:64-72. DOI: 10.1016/j.peptides.2015.04.017. View

16.

Min H, Yun H, Ji S, Rajasekaran G, Kim J, Kim J . Rattusin structure reveals a novel defensin scaffold formed by intermolecular disulfide exchanges. Sci Rep. 2017; 7:45282. PMC: 5366907. DOI: 10.1038/srep45282. View

17.

Feng Y, Geng Y, Zhou T, Wang J . NMR structure note: human esophageal cancer-related gene 2. J Biomol NMR. 2012; 53(1):65-70. DOI: 10.1007/s10858-012-9622-9. View

18.

Bohmer A, Barz S, Schwab K, Kolbe U, Gabel A, Kirkpatrick J . Modulation of FLT3 signal transduction through cytoplasmic cysteine residues indicates the potential for redox regulation. Redox Biol. 2019; 28:101325. PMC: 6812047. DOI: 10.1016/j.redox.2019.101325. View

19.

Dombkowski A, Sultana K, Craig D . Protein disulfide engineering. FEBS Lett. 2013; 588(2):206-12. DOI: 10.1016/j.febslet.2013.11.024. View

20.

Wang M, Herrmann C, Simonovic M, Szklarczyk D, von Mering C . Version 4.0 of PaxDb: Protein abundance data, integrated across model organisms, tissues, and cell-lines. Proteomics. 2015; 15(18):3163-8. PMC: 6680238. DOI: 10.1002/pmic.201400441. View