Complex lasso proteins explained

Complex lasso proteins (also called pierced lasso bundles or tadpoles) are proteins in which a covalent loop (portion of the backbone closed with a covalent bridge) is pierced by another piece of the backbone. Subclass of complex lasso proteins are Lasso peptides in which the loop is formed by post-translational amide bridge.^{[1] [2]}

Classification of complex lassos

Complex lassos can be divided according to the number of piercings through the minimal surface spanned on the covalent loop.^{[3] [4]} In particular, four classes of complex lasso proteins exist:

• the L_n class (simple lasso), where one tail pierces the surface n times;
• the LS_n class (the supercoiling lasso), where one tail pierces the surface n times, winding around the loop;
• the LL_i,j class (double lasso), where both tails pierce the surface i and j times respectively;
• the LSL_i,j class, where one tail pierces the surface i times in the supercoiling manner, and the second pierces the surface in the simple manner.

Another classification may be given according to the nature of the bridge closing the covalent loop. Most of the complex lasso proteins have a disulfide-based loop, however, the amide-based (lasso peptides) and ester-based complex lasso proteins are known.

Popularity of complex lasso in proteins

Around 18% of proteins with disulfide bridges have complex lasso, however, much more complex lasso would be predicted when analyzing the non-interacting polymeric models.^[5] Apart from structures with only one pierced loop, there may be also chains with several complex lasso structures. In particular, the loops may pierce each other, forming a protein Hopf link.^[6] There are much less complex lassos in proteins than it is expected from simple polymer models. However, there are groups of proteins which have higher complex lasso probability than we could expect from such models.

Biological role

It is not known if the complex lasso motif is functional in general. However, in some cases the importance of the motif for the protein function was reported. In particular, in case of lasso peptides, the motif allows to act like a plug for specific NTP-uptake channels.^{[7] [8] [9]} The motif has also shown significant inhibitory activities against cancer cell invasion and migration.^[10] This migration inhibition is found in cyclized isomers of the peptide regardless of whether the tail is threaded or not, suggesting the function arises from the cyclization of the peptide and not the lasso motif.^[11] On the other hand, the motif was shown to be functional in case of leptin - the obesity-related protein.^[12] The analysis of the shape of complex lasso proteins compared to the polymeric models with similar size shows, that some classes of complex lasso proteins may also be functional. This concerns toxic, antimicrobial, defensin-like or immune system related with L₁ motif

Computer tools to analyze the complex lasso topology

The current list of complex lasso proteins may be found in the LassoProt database, which allows also uploading and analyzing own data. The manual inspection of the data is also possible with the PyLasso^[13] - the PyMol plugin.

See also

Knotted proteins

Notes and References

1. Book: Lasso Peptides. Li. Yanyan. Zirah. Séverine. Rebuffat. Sylvie. 2015. Springer New York. 9781493910090. SpringerBriefs in Microbiology. New York, NY. 10.1007/978-1-4939-1010-6. 20581160 .
2. Maksimov. Mikhail O.. Pan. Si Jia. James Link. A.. 2012. Lasso peptides: structure, function, biosynthesis, and engineering. Natural Product Reports. 29. 9. 996–1006. 10.1039/c2np20070h. 22833149. 0265-0568.
3. Niemyska. Wanda. Dabrowski-Tumanski. Pawel. Kadlof. Michal. Haglund. Ellinor. Sułkowski. Piotr. Sulkowska. Joanna I.. 2016-11-22. Complex lasso: new entangled motifs in proteins. Scientific Reports. 6. 1. 36895. 10.1038/srep36895. 2045-2322. 5118788. 27874096. 2016NatSR...636895N.
4. Dabrowski-Tumanski. Pawel. Niemyska. Pawel. Pasznik. Pawel. Sulkowska. Joanna I.. 2016-04-29. LassoProt: server to analyze biopolymers with lassos. Nucleic Acids Research. 44. W1. W383–W389. 10.1093/nar/gkw308. 27131383. 1362-4962. 4987892.
5. Dabrowski-Tumanski. Pawel. Gren. Bartosz. Sulkowska. Joanna I.. 2019-04-17. Statistical Properties of Lasso-Shape Polymers and Their Implications for Complex Lasso Proteins Function. Polymers. 11. 4. 707. 10.3390/polym11040707. 30999683. 6523798. 2073-4360 . free .
6. Dabrowski-Tumanski. Pawel. Sulkowska. Joanna I.. 2017-03-28. Topological knots and links in proteins. Proceedings of the National Academy of Sciences. 114. 13. 3415–3420. 10.1073/pnas.1615862114. 0027-8424. 5380043. 28280100 . free .
7. Knappe. Thomas A.. Linne. Uwe. Zirah. Séverine. Rebuffat. Sylvie. Xie. Xiulan. Marahiel. Mohamed A.. August 2008. Isolation and Structural Characterization of Capistruin, a Lasso Peptide Predicted from the Genome Sequence of Burkholderia thailandensis E264. Journal of the American Chemical Society. 130. 34. 11446–11454. 10.1021/ja802966g. 18671394. 5327111 . 0002-7863.
8. Pan. Si Jia. Link. A. James. 2011-04-06. Sequence Diversity in the Lasso Peptide Framework: Discovery of Functional Microcin J25 Variants with Multiple Amino Acid Substitutions. Journal of the American Chemical Society. 133. 13. 5016–5023. 10.1021/ja1109634. 21391585. 0002-7863.
9. Hegemann. Julian D.. Zimmermann. Marcel. Xie. Xiulan. Marahiel. Mohamed A.. 2015-07-21. Lasso Peptides: An Intriguing Class of Bacterial Natural Products. Accounts of Chemical Research. 48. 7. 1909–1919. 10.1021/acs.accounts.5b00156. 26079760. 0001-4842.
10. Son . Sangkeun . Jang . Mina . Lee . Byeongsan . Hong . Young-Soo . Ko . Sung-Kyun . Jang . Jae-Hyuk . Ahn . Jong Seog . 2018-10-26 . Ulleungdin, a Lasso Peptide with Cancer Cell Migration Inhibitory Activity Discovered by the Genome Mining Approach . Journal of Natural Products . en . 81 . 10 . 2205–2211 . 10.1021/acs.jnatprod.8b00449 . 0163-3864.
11. Digal . Lori . Samson . Shiela C. . Stevens . Mark A. . Ghorai . Abhijit . Kim . Hyungyu . Mifflin . Marcus C. . Carney . Keith R. . Williamson . David L. . Um . Soohyun . Nagy . Gabe . Oh . Dong-Chan . Mendoza . Michelle C. . Roberts . Andrew G. . 2024-01-19 . Nonthreaded Isomers of Sungsanpin and Ulleungdin Lasso Peptides Inhibit H1299 Cancer Cell Migration . ACS Chemical Biology . en . 19 . 1 . 81–88 . 10.1021/acschembio.3c00525 . 1554-8929.
12. Haglund. Ellinor. Pilko. Anna. Wollman. Roy. Jennings. Patricia Ann. Onuchic. Jose Nelson. 2016-12-30. Pierced Lasso Topology Controls Function in Leptin. The Journal of Physical Chemistry B. 121. 4. 706–718. 10.1021/acs.jpcb.6b11506. 28035835. 4680168 .
13. Gierut. Aleksandra M. Niemyska. Wanda. Dabrowski-Tumanski. Pawel. Sułkowski. Piotr. Sulkowska. Joanna I. 2017-12-01. Valencia. Alfonso. PyLasso: a PyMOL plugin to identify lassos. Bioinformatics. 33. 23. 3819–3821. 10.1093/bioinformatics/btx493. 28961868. 1367-4803. free.