Mechanoradicals in tensed tendon collagen as a source of oxidative stress.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 05 2020
08 05 2020
Historique:
received:
15
05
2019
accepted:
10
03
2020
entrez:
10
5
2020
pubmed:
10
5
2020
medline:
18
8
2020
Statut:
epublish
Résumé
As established nearly a century ago, mechanoradicals originate from homolytic bond scission in polymers. The existence, nature and biological relevance of mechanoradicals in proteins, instead, are unknown. We here show that mechanical stress on collagen produces radicals and subsequently reactive oxygen species, essential biological signaling molecules. Electron-paramagnetic resonance (EPR) spectroscopy of stretched rat tail tendon, atomistic molecular dynamics simulations and quantum-chemical calculations show that the radicals form by bond scission in the direct vicinity of crosslinks in collagen. Radicals migrate to adjacent clusters of aromatic residues and stabilize on oxidized tyrosyl radicals, giving rise to a distinct EPR spectrum consistent with a stable dihydroxyphenylalanine (DOPA) radical. The protein mechanoradicals, as a yet undiscovered source of oxidative stress, finally convert into hydrogen peroxide. Our study suggests collagen I to have evolved as a radical sponge against mechano-oxidative damage and proposes a mechanism for exercise-induced oxidative stress and redox-mediated pathophysiological processes.
Identifiants
pubmed: 32385229
doi: 10.1038/s41467-020-15567-4
pii: 10.1038/s41467-020-15567-4
pmc: PMC7210969
doi:
Substances chimiques
Biocompatible Materials
0
Biopolymers
0
Free Radicals
0
Reactive Oxygen Species
0
Dihydroxyphenylalanine
63-84-3
Collagen
9007-34-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2315Références
Staudinger, E. & Leupold, H. Über Isopren und Kautschuk, 18. Mitteil.: Viscosittäts-Untersuchungen an Balata. Ber. Dtsch. Chem. Ges. 63, 730–733 (1930).
doi: 10.1002/cber.19300630329
Caruso, M. M. et al. Mechanically-induced chemical changes in polymeric materials. Chem. Rev. 109, 5755–98 (2009).
pubmed: 19827748
doi: 10.1021/cr9001353
Fitch, K. R. & Goodwin, A. P. Mechanochemical reaction cascade for sensitive detection of covalent bond breakage in hydrogels. Chem. Mater. 26, 6771–6776 (2014).
doi: 10.1021/cm503253n
Baytekin, H. T., Baytekin, B. & Grzybowski, B. A. Mechanoradicals created in "polymeric sponges" drive reactions in aqueous media. Angew. Chem. Int. Ed. Engl. 51, 3596–600 (2012).
pubmed: 22383092
doi: 10.1002/anie.201108110
Fang, F. & Lake, S. P. Experimental evaluation of multiscale tendon mechanics. J. Orthop. Res. 35, 1353–1365 (2017).
pubmed: 27878999
doi: 10.1002/jor.23488
Fratzl, P. Collagen - Structure and Mechanics. (Springer, US, 2008).
Bühler, M. J. Nature designs tough collagen: explaining the nanostructure of collagen fibrils. Proc. Natl Acad. Sci. USA 103, 12285–90 (2006).
doi: 10.1073/pnas.0603216103
Depalle, B., Qin, Z., Shefelbine, S. J. & Bühler, M. J. Influence of cross-link structure, density and mechanical properties in the mesoscale deformation mechanisms of collagen fibrils. J. Mech. Behav. Biomed. Mater. 52, 1–13 (2015).
pubmed: 25153614
pmcid: 4653952
doi: 10.1016/j.jmbbm.2014.07.008
Gautieri, A., Vesentini, S., Redaelli, A. & Bühler, M. J. Hierarchical structure and nanomechanics of collagen microfibrils from the atomistic scale up. Nano Lett. 11, 757–766 (2011).
pubmed: 21207932
doi: 10.1021/nl103943u
Masic, A. et al. Osmotic pressure induced tensile forces in tendon collagen. Nat. Commun. 6, 5942 (2015).
pubmed: 25608644
pmcid: 4354200
doi: 10.1038/ncomms6942
Misof, K., Rapp, G. & Fratzl, P. A new molecular model for collagen elasticity based on synchrotron x-ray scattering evidence. Biophys. J. 72, 1376–81 (1997).
pubmed: 9138582
pmcid: 1184519
doi: 10.1016/S0006-3495(97)78783-6
Puxkandl, R. et al. Viscoelastic properties of collagen: synchrotron radiation investigations and structural model. Philos. Trans. R Soc. Lond. B Biol. Sci. 357, 191–7 (2002).
pubmed: 11911776
pmcid: 1692933
doi: 10.1098/rstb.2001.1033
Zitnay, J. L. et al. Molecular level detection and localization of mechanical damage in collagen enabled by collagen hybridizing peptides. Nat. Commun. 8, 14913 (2017).
pubmed: 28327610
pmcid: 5364439
doi: 10.1038/ncomms14913
Varma, S., Orgel, J. P. & Schieber, J. D. Nanomechanics of type I collagen. Biophys. J. 111, 50–6 (2016).
pubmed: 27410733
pmcid: 4945622
doi: 10.1016/j.bpj.2016.05.038
Chandra, H. & Symons, M. C. Sulphur radicals formed by cutting alpha-keratin. Nature 328, 833–4 (1987).
pubmed: 2442616
doi: 10.1038/328833a0
Symons, M. C. Radicals generated by bone cutting and fracture. Free Radic. Biol. Med. 20, 831–5 (1996).
pubmed: 8728031
doi: 10.1016/0891-5849(95)02174-4
Komi, P. V. Relevance of in vivo force measurements to human biomechanics. J. Biomech. 23, 27–34 (1990).
doi: 10.1016/0021-9290(90)90038-5
Zhurkov, S. N., Savostin, A. Y. & Tomashevskiy, È. E. The mechanism behind the breakdown of polymers investigated by means of electron spin resonance. In Proc. Doklady Akademii Nauk Vol. 159, 303–305 (Russian Academy of Sciences, 1964).
Beyer, M. K. & Clausen-Schaumann, H. Mechanochemistry: the mechanical activation of covalent bonds. Chem. Rev. 105, 2921–48 (2005).
pubmed: 16092823
doi: 10.1021/cr030697h
Marino, A. & Becker, R. Temperature dependence of the epr signal in tendon collagen. Nature 222, 164 (1969).
pubmed: 4304924
doi: 10.1038/222164b0
Orgel, J. P., Irving, T. C., Miller, A. & Wess, T. J. Microfibrillar structure of type I collagen in situ. Proc. Natl Acad. Sci. USA 103, 9001–5 (2006).
pubmed: 16751282
doi: 10.1073/pnas.0502718103
Hodge, A. & Petruska, J. Recent Studies with the Electron Microscope on Ordered Aggregates of the Tropocollagen Molecule, 289–300 (Academic Press, New York, 1963).
Eyre, D. R., Weis, M. A. & Wu, J. J. Advances in collagen cross-link analysis. Methods 45, 65–74 (2008).
pubmed: 18442706
pmcid: 2398701
doi: 10.1016/j.ymeth.2008.01.002
Costescu, B. I. & Gräter, F. Time-resolved force distribution analysis. BMC Biophys. 6, 5 (2013).
pubmed: 24499624
pmcid: 3669045
doi: 10.1186/2046-1682-6-5
Rennekamp, B., Kutzki, F., Obarska-Kosinska, A., Zapp, C. & Gräter, F. Hybrid kinetic monte carlo/molecular dynamics simulations of bond scissions in proteins. J. Chem. Theory Comput. https://doi.org/10.1021/acs.jctc.9b00786 (2019).
Luo, Y.-R. Comprehensive Handbook of Chemical Bond Energies (CRC press, 2007).
Nick, T. U., Ravichandran, K. R., Stubbe, J., Kasanmascheff, M. & Bennati, M. Spectroscopic evidence for a H bond network at Y356 located at the subunit interface of active E. coli ribonucleotide reductase. Biochemistry 56, 3647–3656 (2017).
pubmed: 28640584
doi: 10.1021/acs.biochem.7b00462
Srinivas, V. et al. Metal-free ribonucleotide reduction powered by a dopa radical in mycoplasma pathogens. Nature 563, 416–420 (2018).
pubmed: 30429545
pmcid: 6317698
doi: 10.1038/s41586-018-0653-6
Blaesi, E. J. et al. Metal-free class Ie ribonucleotide reductase from pathogens initiates catalysis with a tyrosine-derived dihydroxyphenylalanine radical. Proc. Natl Acad. Sci. 115, 10022–10027 (2018).
pubmed: 30224458
doi: 10.1073/pnas.1811993115
Kaupp, M., Remenyi, C., Vaara, J., Malkina, O. L. & Malkin, V. G. Density functional calculations of electronic g-tensors for semiquinone radical anions. the role of hydrogen bonding and substituent effects. J. Am. Chem. Soc. 124, 2709–2722 (2002).
pubmed: 11890822
doi: 10.1021/ja0162764
Dean, R. T., Gieseg, S. & Davies, M. J. Reactive species and their accumulation on radical-damaged proteins. Trends Biochem. Sci. 18, 437–441 (1993).
pubmed: 8291091
doi: 10.1016/0968-0004(93)90145-D
Winkler, J. R. & Gray, H. B. Electron flow through biological molecules: does hole hopping protect proteins from oxidative damage? Q. Rev. Biophys. 48, 411–420 (2015).
pubmed: 26537399
pmcid: 4793975
doi: 10.1017/S0033583515000062
Aktah, D. & Frank, I. Breaking bonds by mechanical stress: when do electrons decide for the other side? J. Am. Chem. Soc. 124, 3402–6 (2002).
pubmed: 11916426
doi: 10.1021/ja004010b
Dopieralski, P., Ribas-Arino, J., Anjukandi, P., Krupicka, M. & Marx, D. Unexpected mechanochemical complexity in the mechanistic scenarios of disulfide bond reduction in alkaline solution. Nat. Chem. 9, 164–170 (2017).
pubmed: 28282046
doi: 10.1038/nchem.2632
Pill, M. F., Schmidt, S. W., Beyer, M. K., Clausen-Schaumann, H. & Kersch, A. A density functional theory model of mechanically activated silyl ester hydrolysis. J. Chem. Phys. 140, 044321 (2014).
pubmed: 25669537
doi: 10.1063/1.4862827
McDowell, L. M., Burzio, L. A., Waite, J. H. & Schaefer, J. Rotational echo double resonance detection of cross-links formed in mussel byssus under high-flow stress. J. Biol. Chem. 274, 20293–20295 (1999).
pubmed: 10400649
doi: 10.1074/jbc.274.29.20293
Kato, Y., Uchida, K. & Kawakishi, S. Aggregation of collagen exposed to uva in the presence of riboflavin: a plausible role of tyrosine modification. Photochem. Photobiol. 59, 343–349 (1994).
pubmed: 8016214
doi: 10.1111/j.1751-1097.1994.tb05045.x
Carr, A. C., Bozonet, S. M., Pullar, J. M., Simcock, J. W. & Vissers, M. C. Human skeletal muscle ascorbate is highly responsive to changes in vitamin c intake and plasma concentrations. Am. J. Clin. Nutr. 97, 800–807 (2013).
pubmed: 23446899
pmcid: 3607654
doi: 10.3945/ajcn.112.053207
Li, Y., Jongberg, S., Andersen, M. L., Davies, M. J. & Lund, M. N. Quinone-induced protein modifications: kinetic preference for reaction of 1, 2-benzoquinones with thiol groups in proteins. Free Rad. Biol. Med. 97, 148–157 (2016).
pubmed: 27212016
doi: 10.1016/j.freeradbiomed.2016.05.019
Harrington, M. J., Masic, A., Holten-Andersen, N., Waite, J. H. & Fratzl, P. Iron-clad fibers: a metal-based biological strategy for hard flexible coatings. Science 328, 216–220 (2010).
pubmed: 20203014
pmcid: 3087814
doi: 10.1126/science.1181044
Jackson, M. J., Vasilaki, A. & McArdle, A. Cellular mechanisms underlying oxidative stress in human exercise. Free Radic. Biol. Med. 98, 13–17 (2016).
pubmed: 26912036
doi: 10.1016/j.freeradbiomed.2016.02.023
Hertel, M. M., Denysenkov, V. P., Bennati, M. & Prisner, T. F. Pulsed 180-ghz epr/endor/peldor spectroscopy. Magn. Reson. Chem. 43, S248–S255 (2005).
pubmed: 16235223
doi: 10.1002/mrc.1681
Rainey, J. K. & Goh, M. C. An interactive triple-helical collagen builder. Bioinformatics 20, 2458–2459 (2004).
pubmed: 15073022
doi: 10.1093/bioinformatics/bth247
Šali, A. & Blundell, T. L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779–815 (1993).
pubmed: 8254673
doi: 10.1006/jmbi.1993.1626
Nivón, L. G., Moretti, R. & Baker, D. A pareto-optimal refinement method for protein design scaffolds. PLoS ONE 8, e59004 (2013).
pubmed: 23565140
pmcid: 3614904
doi: 10.1371/journal.pone.0059004
Conway, P., Tyka, M. D., Di Maio, F., Konerding, D. E. & Baker, D. Relaxation of backbone bond geometry improves protein energy landscape modeling. Protein Sci. 23, 47–55 (2014).
pubmed: 24265211
doi: 10.1002/pro.2389
Abraham, M. J. et al. Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1, 19–25 (2015).
doi: 10.1016/j.softx.2015.06.001
Schrödinger Release 2016-2: Maestro, version 10.6 (Schrödinger LLC, New York, NY, 2016).
Frisch, M. J. et al. Gaussian 09, revision D. 01 (Gaussian Inc. Wallingford, CT, 2013).
Lee, C., Yang, W. & Parr, R. G. Development of the colle-salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 37, 785 (1988).
doi: 10.1103/PhysRevB.37.785
Becke, A. D. Density-functional thermochemistry. iii. the role of exact exchange. J. Chem. Phys. 98, 5648–5652 (1993).
doi: 10.1063/1.464913
Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A. & Case, D. A. Development and testing of a general amber force field. J. Comput. Chem. 25, 1157–1174 (2004).
pubmed: 15116359
doi: 10.1002/jcc.20035
Wang, J., Wang, W., Kollman, P. A. & Case, D. A. Automatic atom type and bond type perception in molecular mechanical calculations. J. Mol. Graph. Model. 25, 247–260 (2006).
pubmed: 16458552
doi: 10.1016/j.jmgm.2005.12.005
daSilva, A. W. S. & Vranken, W. F. Acpype-antechamber python parser interface. BMC Res. Notes 5, 367 (2012).
doi: 10.1186/1756-0500-5-367
Best, R. B. & Hummer, G. Optimized molecular dynamics force fields applied to the helix- coil transition of polypeptides. J. Phys. Chem. B 113, 9004–9015 (2009).
pubmed: 19514729
pmcid: 3115786
doi: 10.1021/jp901540t
Lindorff-Larsen, K. et al. Improved side-chain torsion potentials for the amber ff99sb protein force field. Proteins 78, 1950–1958 (2010).
pubmed: 20408171
pmcid: 2970904
Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983).
doi: 10.1063/1.445869
Bussi, G., Donadio, D. & Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 126, 014101 (2007).
doi: 10.1063/1.2408420
Parrinello, M. & Rahman, A. Polymorphic transitions in single crystals: a new molecular dynamics method. J. Appl. Phys. 52, 7182–7190 (1981).
doi: 10.1063/1.328693
Darden, T., York, D. & Pedersen, L. Particle mesh ewald: An n log (n) method for ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993).
doi: 10.1063/1.464397
Hess, B. P.-lincs A parallel linear constraint solver for molecular simulation. J. Chem. Theory Comput. 4, 116–122 (2008).
pubmed: 26619985
doi: 10.1021/ct700200b
Kutzner, C., Czub, J. & Grubmuller, H. Keep it flexible: Driving macromolecular rotary motions in atomistic simulations with gromacs. J. Chem. Theory Comput. 7, 1381–1393 (2011).
pubmed: 21566696
pmcid: 3091370
doi: 10.1021/ct100666v
Huerta-Cepas, J. et al. eggNOG 4.5: a hierarchical orthology framework with improved functional annotations for eukaryotic, prokaryotic and viral sequences. Nucleic Acids Res. 44, D286–D293 (2015).
pubmed: 26582926
pmcid: 4702882
doi: 10.1093/nar/gkv1248
Frickey, T. & Lupas, A. Clans: a java application for visualizing protein families based on pairwise similarity. Bioinformatics 20, 3702–3704 (2004).
pubmed: 15284097
doi: 10.1093/bioinformatics/bth444
Katoh, K., Misawa, K., Kuma, K.-i & Miyata, T. Mafft: a novel method for rapid multiple sequence alignment based on fast fourier transform. Nucleic Acids Res. 30, 3059–3066 (2002).
pubmed: 12136088
pmcid: 135756
doi: 10.1093/nar/gkf436
Pettersen, E. F. et al. UCSF Chimera-?a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).
pubmed: 15264254
pmcid: 15264254
doi: 10.1002/jcc.20084
Dunning Jr, T. H. Gaussian basis sets for use in correlated molecular calculations. i. the atoms boron through neon and hydrogen. J. Chem. Phys. 90, 1007–1023 (1989).
doi: 10.1063/1.456153
Aquilante, F. et al. Molcas 8: New capabilities for multiconfigurational quantum chemical calculations across the periodic table. J. Comput. Chem. 37, 506–541 (2016).
pubmed: 26561362
doi: 10.1002/jcc.24221
Neese, F. Software update: the orca program system, version 4.0. Wiley Interdiscip. Revi. Comput. Mol. Sci. 8, e1327 (2018).
Hudson, D. M., Archer, M., King, K. B. & Eyre, D. R. Glycation of type I collagen selectively targets the same helical domain lysine sites as lysyl oxidase-mediated cross-linking. J. Biol. Chem. 293, 15620–15627 (2018).
pubmed: 30143533
pmcid: 6177574
doi: 10.1074/jbc.RA118.004829
Weis, M. A. et al. Location of 3-hydroxyproline residues in collagen types I, II, III, and V/XI implies a role in fibril supramolecular assembly. J. Biol. Chem. 285, 2580–2590 (2010).
pubmed: 19940144
doi: 10.1074/jbc.M109.068726
Hudson, D. M. et al. Post-translationally abnormal collagens of prolyl 3-hydroxylase-2 null mice offer a pathobiological mechanism for the high myopia linked to human leprel1 mutations. J. Biol. Chem. 290, 8613–8622 (2015).
pubmed: 25645914
pmcid: 4375510
doi: 10.1074/jbc.M114.634915