Complex lasso proteins

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]

## Contents

* 1 Classification of complex lassos
* 2 Popularity of complex lasso in proteins
* 3 Biological role
* 4 Computer tools to analyze the complex lasso topology
* 5 See also
* 6 References

## Classification of complex lassos

Some lasso motifs present in protein structures[3].

Complex lassos can be divided according to the number of piercings through the minimal surface spanned on the covalent loop.[4][5] In particular, four classes of complex lasso proteins exist:

* the Ln class (simple lasso), where one tail pierces the surface n times;
* the LSn class (the supercoiling lasso), where one tail pierces the surface n times, winding around the loop;
* the LLi,j class (double lasso), where both tails pierce the surface i and j times respectively;
* the LSLi,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 also known.[5]

Complex lassos can coexist with other protein topologies. An analysis performed on the structures predicted by the AlphaFold found examples of knotted lasso proteins.[6] The knots were present not only on the tail part of the lasso, but also on the loop itself. These motifs can be found in the membrane proteins.

## Popularity of complex lasso in proteins

Around 18% of proteins with disulfide bridges have complex lasso,[4][5] however, much more complex lasso would be predicted when analyzing the non-interacting polymeric models.[7] 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.[8] 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.

Over 2.2 million complex lasso motifs were found in the AlphaFold-predicted proteins.[9] The result of this search is available in the database section of the AlphaLasso web server.

## 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.[10][11][12] The motif has also shown significant inhibitory activities against cancer cell invasion and migration.[13] However, multiple cyclized isomers of the peptide display this migration inhibition, suggesting the function arises from the cyclization of the peptide and not the lasso motif.[14] On the other hand, the motif was shown to be functional in case of leptin \- the obesity-related protein.[15] 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[7]

## Computer tools to analyze the complex lasso topology

The current list of experimentally obtained complex lasso proteins may be found in the LassoProt database,[5] which allows also uploading and analyzing own data. The AlphaLasso web server enables analysis of AI-predicted protein structures and provides a database of disulfide-based loops in the AlphaFold-predicted models.[9] The manual inspection of the data is also possible with the PyLasso[16] \- a PyMol plugin.

## See also

Knotted proteins

## References

1. ↑ Li, Yanyan; Zirah, Séverine; Rebuffat, Sylvie (2015). Lasso Peptides. SpringerBriefs in Microbiology. New York, NY: Springer New York. doi:10.1007/978-1-4939-1010-6. ISBN 978-1-4939-1009-0.
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. doi:10.1039/c2np20070h. ISSN 0265-0568. PMID 22833149.
3. ↑ Dabrowski-Tumanski, Pawel; Sulkowska, Joanna (2017-09-16). "To Tie or Not to Tie? That Is the Question". Polymers 9 (12): 454. doi:10.3390/polym9090454. ISSN 2073-4360. PMID 30965758.
4. ↑ 4.0 4.1 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). doi:10.1038/srep36895. ISSN 2045-2322. PMID 27874096. Bibcode: 2016NatSR...636895N.
5. ↑ 5.0 5.1 5.2 5.3 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. doi:10.1093/nar/gkw308. ISSN 1362-4962. PMID 27131383.
6. ↑ da Silva, Fernando Bruno; Perlinska, Agata P.; Płonka, Jacek; Flapan, Erica; Sulkowska, Joanna I. (2025-05-19). "Universe of Lasso Proteins: Exploring the limit of entanglement of protein predicted by AlphaFold". Journal of Molecular Biology. doi:10.1016/j.jmb.2025.169217. ISSN 0022-2836. https://linkinghub.elsevier.com/retrieve/pii/S0022283625002839.
7. ↑ 7.0 7.1 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. doi:10.3390/polym11040707. ISSN 2073-4360. PMID 30999683.
8. ↑ 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. doi:10.1073/pnas.1615862114. ISSN 0027-8424. PMID 28280100.
9. ↑ 9.0 9.1 Rubach, Pawel; Płonka, Jacek; Gren, Bartosz A.; Bruno da Silva, Fernando; Korpacz, Marta; Sulkowska, Joanna I. (2025-05-07). "AlphaLasso—a web server to identify loop and lasso motifs in 3D structure of biopolymers". Nucleic Acids Research. doi:10.1093/nar/gkaf375. ISSN 1362-4962. PMC 12230674. https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkaf375/8126259.
10. ↑ 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. doi:10.1021/ja802966g. ISSN 0002-7863. PMID 18671394.
11. ↑ 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. doi:10.1021/ja1109634. ISSN 0002-7863. PMID 21391585.
12. ↑ 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. doi:10.1021/acs.accounts.5b00156. ISSN 0001-4842. PMID 26079760.
13. ↑ 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" (in en). Journal of Natural Products 81 (10): 2205–2211. doi:10.1021/acs.jnatprod.8b00449. ISSN 0163-3864. https://pubs.acs.org/doi/10.1021/acs.jnatprod.8b00449.
14. ↑ Digal, Lori; Samson, Shiela C.; Stevens, Mark A.; Ghorai, Abhijit; Kim, Hyungyu; Mifflin, Marcus C.; Carney, Keith R.; Williamson, David L. et al. (2024-01-19). "Nonthreaded Isomers of Sungsanpin and Ulleungdin Lasso Peptides Inhibit H1299 Cancer Cell Migration" (in en). ACS Chemical Biology 19 (1): 81–88. doi:10.1021/acschembio.3c00525. ISSN 1554-8929. PMC 11832225. https://pubs.acs.org/doi/10.1021/acschembio.3c00525.
15. ↑ 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. doi:10.1021/acs.jpcb.6b11506. PMID 28035835. http://www.escholarship.org/uc/item/62z7s7v0.
16. ↑ Gierut, Aleksandra M; Niemyska, Wanda; Dabrowski-Tumanski, Pawel; Sułkowski, Piotr; Sulkowska, Joanna I (2017-12-01). Valencia, Alfonso. ed. "PyLasso: a PyMOL plugin to identify lassos". Bioinformatics 33 (23): 3819–3821. doi:10.1093/bioinformatics/btx493. ISSN 1367-4803. PMID 28961868.

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