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However, many characterized RiPP proteases require specific core peptide modifications prior to cleavage, limiting their broader applicability. Here, we identified a cyanobactin protease clade that efficiently processes diverse peptide substrates while maintaining strict recognition-sequence selectivity. We demonstrated that GusA, a representative member of this clade, can be used for the processing of structurally complex modified peptides and the removal of affinity tags from recombinant proteins. GusA-mediated exposure of N-terminal cysteine residues can also be applied to the construction of chemically diversified asymmetric phage-displayed macrocyclic peptide libraries, from which nanomolar-affinity ligands against Keap1 and Bcl-xL were identified, providing valuable tools for biological studies and potential therapeutics. The same strategy was further applied to site-selective and multicolor labeling of mammalian cell-surface proteins, demonstrating that GusA-mediated N-terminal cysteine generation can be readily integrated with bioorthogonal labeling chemistries. Together, our results establish cyanobactin proteases as an underexplored source of sequence-selective biocatalysts for site-selective peptide and protein modification.<\/jats:p>","DOI":"10.1021\/jacs.6c14243","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:01:58Z","timestamp":1791460918000},"page":"44798-44810","source":"Crossref","is-referenced-by-count":0,"title":["Sequence Similarity\nNetwork-Guided Discovery of a\nSequence-Tolerant Cyanobactin Protease Clade for Site-Selective Peptide\nand Protein Modification"],"prefix":"10.1021","volume":"148","author":[{"given":"Yukun","family":"Zhou","sequence":"first","affiliation":[{"name":"Sun Yat-Sen University Shenzhen Campus , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangzhao","family":"Xiao","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University Shenzhen Campus , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sicong","family":"Yao","sequence":"additional","affiliation":[{"name":"Shenzhen Bay Laboratory , , ,","place":["Shenzhen, China, 518132"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University Shenzhen Campus , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongqin","family":"Yang","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University Shenzhen Campus , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghui","family":"Yang","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University Shenzhen Campus , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoman","family":"Liu","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University Shenzhen Campus , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmei","family":"Wang","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University Shenzhen Campus , , ,","place":["Shenzhen, China, 518107"]},{"name":"Guangzhou Medical University , , ,","place":["Guangzhou, China, 511300"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yapei","family":"Wu","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University Shenzhen Campus , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9759-2417","authenticated-orcid":true,"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University Shenzhen Campus , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0589-5088","authenticated-orcid":true,"given":"Yu-Hsuan","family":"Tsai","sequence":"additional","affiliation":[{"name":"Shenzhen Bay Laboratory , , ,","place":["Shenzhen, China, 518132"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4587-4962","authenticated-orcid":true,"given":"Yiwu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University Shenzhen Campus , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"issue":"4","key":"2026102111091570000_cit1","doi-asserted-by":"publisher","DOI":"10.3390\/jmp6040032","article-title":"Molecular Perspective\non Proteases: Regulation of Programmed Cell Death Signaling, Inflammation\nand Pathological Outcomes","volume":"6","author":"Ansari","year":"2025","journal-title":"J. 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Rev."},{"issue":"2","key":"2026102111091570000_cit4","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.pep.2011.08.005","article-title":"An overview\nof enzymatic reagents for the removal of affinity tags","volume":"80","author":"Waugh","year":"2011","journal-title":"Protein Expression Purif."},{"issue":"1","key":"2026102111091570000_cit5","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1021\/acsbiomedchemau.3c00059","article-title":"Proteases\nInvolved in Leader Peptide Removal during\nRiPP Biosynthesis","volume":"4","author":"Eslami","year":"2024","journal-title":"ACS Bio Med. Chem. Au"},{"issue":"1","key":"2026102111091570000_cit6","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/s41589-025-02063-3","article-title":"A gasdermin-based\nlife\u2013death evolution system for reprogramming\nprotease specificity","volume":"22","author":"Gao","year":"2026","journal-title":"Nat. Chem. 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U.S.A."},{"issue":"22","key":"2026102111091570000_cit43","doi-asserted-by":"publisher","first-page":"6975","DOI":"10.1021\/jacs.5b04681","article-title":"Facile\nRemoval of Leader Peptides from Lanthipeptides by Incorporation of\na Hydroxy Acid","volume":"137","author":"Bindman","year":"2015","journal-title":"J. Am. Chem. Soc."},{"issue":"47","key":"2026102111091570000_cit44","doi-asserted-by":"publisher","first-page":"8935","DOI":"10.1039\/C0CC02945A","article-title":"Photochemical cleavage of leader peptides","volume":"46","author":"Bindman","year":"2010","journal-title":"Chem. Commun."},{"issue":"8","key":"2026102111091570000_cit45","doi-asserted-by":"publisher","first-page":"2338","DOI":"10.1021\/ja109044r","article-title":"Production\nof Lantipeptides in Escherichia coli","volume":"133","author":"Shi","year":"2011","journal-title":"J. Am. Chem. 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