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The essential mycobacterial ClpC1P1P2 protease has received attention as a prospective target for novel antibacterial therapeutics. However, efforts to probe its function in cells are constrained by our limited knowledge of its physiological proteolytic repertoire. Here, we interrogate the role of mycobacterial ClpS in directing N\u2010degron pathway proteolysis by ClpC1P1P2 in\n                    <jats:italic>Mycolicibacterium smegmatis<\/jats:italic>\n                    . Binding assays demonstrate that mycobacterial ClpS binds canonical primary destabilizing residues (Leu, Phe, Tyr, Trp) with moderate affinity. N\u2010degron binding restricts the conformational flexibility of a loop adjacent to the ClpS N\u2010degron binding pocket and strengthens ClpS\u2022ClpC1 binding affinity ~30\u2010fold, providing a mechanism for cells to prioritize N\u2010degron proteolysis when substrates are abundant. Proteolytic reporter assays in\n                    <jats:italic>M. smegmatis<\/jats:italic>\n                    confirm degradation of substrates bearing primary N\u2010degrons, but suggest that secondary N\u2010degrons are absent in mycobacteria. This work expands our understanding of the mycobacterial N\u2010degron pathway and identifies ClpS as a critical component for substrate specificity, providing insights that may support the development of improved Clp protease inhibitors.\n                  <\/jats:p>","DOI":"10.1111\/mmi.15334","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T14:43:43Z","timestamp":1733237023000},"page":"16-30","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>ClpS<\/scp>\n                    Directs Degradation of N\u2010Degron Substrates With Primary Destabilizing Residues in\n                    <i>Mycolicibacterium smegmatis<\/i>"],"prefix":"10.1111","volume":"123","author":[{"given":"Christopher J.","family":"Presloid","sequence":"first","affiliation":[{"name":"Department of Biological Sciences University of Delaware  Newark Delaware 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