Protein crosslinks

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Proteins are linear (unbranched) polypeptide chains of amino acids. The subject of this article is covalent crosslinks between polypeptides, either between protein chains (interchain crosslinks), or within chains (intrachain crosslinks).

Contents

Natural Crosslinks

These crosslinks are formed either spontaneously during protein folding, or as a result of natural enzymatic processes.
For interactive views with sources and further details, click on the first link after each subtitle below.

Detection and Visualization

FirstGlance in Jmol automatically detects and alerts you to the presence of any of the following seven types of covalent protein crosslinks. It provides "one click" tools to zoom in and examine any putative crosslink in detail, including display of the proximal electron density map. See the practical guide FirstGlance/Evaluating Protein Crosslinks.

Disulfide Crosslinks

Disulfide bonds are the most common protein crosslinks. About 23% of protein structures in the PDB have disulfide bonds (July, 2021[1]).

  • Example: Insulin 9ins has 2 interchain and one intrachain disulfide bonds. Additional examples will be found in the lower left panel of FirstGlance when this example is viewed.

Isopeptide Crosslinks

See Isopeptide bonds for a detailed description and examples. An estimate of the frequency of isopeptide crosslinks in the PDB may not be available.

  • A text search for "isopeptide" at RCSB.Org gives ~400 hits (July, 2021).
  • A text search at PDBe gives ~12,000 hits (July, 2021). In a small sample of the latter hits, none contained the term "isopeptide". Also based on a small sample, some entries that contain verified isopeptide bonds do not contain the term (for example, 5jqf).
  • Example: Bacterial pilus adhesin 2xi9 has 2 isopeptide bonds (and 2 thioester bonds). Additional examples will be found in the lower left panel of FirstGlance when this example is viewed.

Thioester Crosslinks

See Thioester protein crosslinks for a detailed description and examples. An estimate of the frequency of thioester crosslinks in the PDB may not be available.

  • A text search for "thioester" at RCSB.Org gives ~2,000 hits (out of ~180,000 total, July, 2021).
  • A text search at PDBe gives ~1,400 hits (July, 2021). Among a sample of 5 of the PDBe hits (the first of every 100 in a listing sorted with best resolution at the top), none had thioester bonds, but most contained terms such as "thioesterase" or "thioester".
  • Adding "and not thioesterase" to the PDBe search reduced the hits to ~500. >30 hits were tested but only a couple had thioester bonds.
  • Example: Bacterial pilus adhesin 2xi9 has 2 thioester bonds (and 2 isopeptide bonds). Additional examples will be found at Thioester protein crosslinks, and in the lower left panel of FirstGlance when this example is viewed.

Thioether Crosslinks

See Thioether protein crosslinks for a detailed description and examples. These include Cys-Tyr crosslinks. Cys-ligand thioether links are common but do not necessarily crosslink polypeptides. An estimate of the frequency of thioether crosslinks in the PDB may not be available.

  • Example: 6e87 (sulfur-carbon distance 1.83 Å).

Ester Crosslinks

See Ester protein crosslinks for a detailed description and examples. An estimate of the frequency of ester crosslinks in the PDB may not be available. Thr-Gln ester crosslinks were first reported in 2013[2].

  • Example: Bacterial pilus repeat domains 4mkm has 2 interchain Thr-Gln ester bonds. Additional examples will be found in the lower left panel of FirstGlance when this example is viewed.

Histidine-tyrosine protein crosslinks

See Histidine-tyrosine protein crosslinks for a detailed description and examples. An estimate of the frequency of ester crosslinks in the PDB may not be available.

Lysine-Cysteine NOS Crosslinks

See Lysine-cysteine NOS bonds for a detailed description and examples. NOS bonds are redox switches in many enzymes. These were most convincingly documented in 2021 by Wensien et al.[3]. They reported that following a search of the entire PDB, they "identified a number of proteins from all domains of life that are highly likely to possess one or more NOS bridges". However, because the existence of NOS bonds has not been widely recognized, they were not modeled in many proteins structures in which they actually occur.

  • Example: 6zx4 was analyzed in depth and provided the first documented case. Additional examples will be found in the lower left panel of FirstGlance when this example is viewed.

Artificial Crosslinks

[To be written - feel free to contribute]

Notes & References

  1. ↑ In July, 2021, the PDB had ~180,000 entries. Advanced search at RCSB.Org for "Polymer molecuar features: polymer entity type = protein" and "Deposited entry features: Disulfide bond count per deposited model > 0" gave ~41,000 hits, or about 23%.
  2. ↑ Kwon H, Squire CJ, Young PG, Baker EN. Autocatalytically generated Thr-Gln ester bond cross-links stabilize the repetitive Ig-domain shaft of a bacterial cell surface adhesin. Proc Natl Acad Sci U S A. 2013 Dec 16. PMID:24344302 doi:http://dx.doi.org/10.1073/pnas.1316855111
  3. ↑ Wensien M, von Pappenheim FR, Funk LM, Kloskowski P, Curth U, Diederichsen U, Uranga J, Ye J, Fang P, Pan KT, Urlaub H, Mata RA, Sautner V, Tittmann K. A lysine-cysteine redox switch with an NOS bridge regulates enzyme function. Nature. 2021 May 5. pii: 10.1038/s41586-021-03513-3. doi:, 10.1038/s41586-021-03513-3. PMID:33953398 doi:http://dx.doi.org/10.1038/s41586-021-03513-3

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Eric Martz

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