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The Mucin-Selective Protease Stce Enables Molecular and Functional Analysis of Human Cancer-Associated Mucins

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The Mucin-Selective Protease Stce Enables Molecular and Functional Analysis of Human Cancer-Associated Mucins The mucin-selective protease StcE enables molecular and functional analysis of human cancer-associated mucins Stacy A. Malakera,1, Kayvon Pedrama,1, Michael J. Ferracaneb, Barbara A. Bensingc, Venkatesh Krishnand, Christian Pette,f, Jin Yue, Elliot C. Woodsa, Jessica R. Kramerg, Ulrika Westerlinde,f, Oliver Dorigod, and Carolyn R. Bertozzia,h,2 aDepartment of Chemistry, Stanford University, Stanford, CA 94305; bDepartment of Chemistry, University of Redlands, Redlands, CA 92373; cDepartment of Medicine, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA 94143; dStanford Women’s Cancer Center, Division of Gynecologic Oncology, Stanford University, Stanford, CA 94305; eLeibniz-Institut für Analytische Wissenschaften (ISAS), 44227 Dortmund, Germany; fDepartment of Chemistry, Umeå University, 901 87 Umeå, Sweden; gDepartment of Bioengineering, University of Utah, Salt Lake City, UT 84112; and hHoward Hughes Medical Institute, Stanford, CA 94305 Edited by Laura L. Kiessling, Massachusetts Institute of Technology, Cambridge, MA, and approved February 25, 2019 (received for review July 30, 2018) Mucin domains are densely O-glycosylated modular protein domains When strung together in “tandem repeats” mucin domains can that are found in a wide variety of cell surface and secreted proteins. form the large structures characteristic of mucin family proteins. Mucin-domain glycoproteins are known to be key players in a host Mucins can be hundreds to thousands of amino acids long of human diseases, especially cancer, wherein mucin expression and and >50% glycosylation by mass (11); MUC16, one of the largest glycosylation patterns are altered. Mucin biology has been difficult mucins, can exceed 22,000 residues and 85% glycosylation by mass to study at the molecular level, in part, because methods to manip- (12), with a persistence length of 1–5 μm (13). Due, in part, to their ulate and structurally characterize mucin domains are lacking. Here, presence at cellular peripheries, mucin family proteins are impor- we demonstrate that secreted protease of C1 esterase inhibitor tant mediators of cell–cell and cell–environment interactions, and (StcE), a bacterial protease from Escherichia coli, cleaves mucin do- have been under scrutiny for years due to their association with mains by recognizing a discrete peptide- and glycan-based motif. We exploited StcE’s unique properties to improve sequence cover- human cancer (14) (which must combat inhibitory cues from its surroundings at every stage of its progression). Indeed, the age, glycosite mapping, and glycoform analysis of recombinant hu- BIOCHEMISTRY man mucins by mass spectrometry. We also found that StcE digests membrane-associated mucin MUC1 is aberrantly expressed in cancer-associated mucins from cultured cells and from ascites ∼60% of all cancers diagnosed each year in the United States fluid derived from patients with ovarian cancer. Finally, using (15), rendering MUC1 one of the most prominently dysregulated StcE, we discovered that sialic acid-binding Ig-type lectin-7 genes in cancer. Functionally, recent work has shown that the (Siglec-7), a glycoimmune checkpoint receptor, selectively binds MUC1 ectodomain alone can drive tumor growth by enhancing sialomucins as biological ligands, whereas the related receptor cancer cell survival and promoting proliferation through biophysical Siglec-9 does not. Mucin-selective proteolysis, as exemplified by pathways (16). The large mucin MUC16 (also called CA-125) is StcE, is therefore a powerful tool for the study of mucin domain highly expressed in ovarian cancer and is used as a clinical bio- structure and function. marker for treatment efficacy and surveillance (17). Observations such as these have motivated numerous efforts toward mucin-based O-glycosylation | mucin | protease | glycoproteomics | Siglec Significance ucin domains are modular protein domains characterized Mby a high frequency of Ser and Thr residues that are O- Mucin-domain glycoproteins are found in nearly every tissue of glycosylated with α-N-acetylgalactosamine (α-GalNAc). The α the human body, and are important in biological processes initial glycosylation with -GalNAc and elaboration to larger ranging from embryogenesis to cancer. Because there are few glycan structures occur through complex, interdependent meta- tools to study mucin domains, their biological functions at the bolic pathways to which hundreds of genes can contribute. The molecular scale remain unclear. Here, we help address a hurdle resulting glycoprotein population is highly heterogeneous and to the study of mucin-domain glycoproteins by characterizing a dynamic, and cannot be predicted based on genomic information bacterial protease with selectivity for mucins. This mucinase alone (1). Dense spacing of these heterogeneous O-glycans “ selectively removes native mucins from cell surfaces and cuts forces the underlying polypeptide to adopt a unique mucin them into fragments amenable to analysis. fold,” which is rigid and extended (2) (Fig. 1A, Left). The mucin fold is found in a wide variety of cell surface and secreted pro- Author contributions: S.A.M., K.P., and C.R.B. designed research; S.A.M., K.P., M.J.F., and teins of various families, analogous to the common Ig fold (3). B.A.B. performed research; V.K., C.P., J.Y., J.R.K., U.W., and O.D. contributed new re- Mucin-domain glycoproteins contribute to many biological agents/analytic tools; S.A.M., K.P., M.J.F., B.A.B., E.C.W., and C.R.B. analyzed data; and processes. For example, they are involved in embryogenesis (4), S.A.M., K.P., and C.R.B. wrote the paper. barrier formation (5), host–pathogen interactions (6), and im- Conflict of interest statement: A patent application relating to the use of enzymes to mune signaling (7). Due to their stiff, elongated, and highly hy- digest mucin-domain glycoproteins has been filed by Stanford University (docket no. STAN-1510PRV). C.R.B. is a cofounder and Scientific Advisory Board member of Palleon drated structures, mucin domains are also important modulators Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent), and of cell- and protein-level biophysics (8). For example, CD45R0 is InterVenn Biosciences, and a member of the Board of Directors of Eli Lilly & Company. a conserved splice variant of the T cell marker CD45, in which O.D. has participated in advisory boards for Tesaro, Merck, and Geneos. O.D. is a speaker three exons encoding mucin domains are missing. The loss of the for Tesaro and AstraZeneca. mucin domains promotes dimerization, abrogating intracellular This article is a PNAS Direct Submission. tyrosine phosphatase activity needed for T cell activation, and Published under the PNAS license. thereby aiding activated T cells in regulated cessation of their 1S.A.M. and K.P. contributed equally to this work. response (9). Mucin domains also serve as receptor ligands. For 2To whom correspondence should be addressed. Email: [email protected]. example, the binding of P-selectin to its ligand, P-selectin gly- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. coprotein ligand-1 (PSGL-1), a mucin-domain glycoprotein, is an 1073/pnas.1813020116/-/DCSupplemental. essential component of leukocyte rolling and adhesion (10). www.pnas.org/cgi/doi/10.1073/pnas.1813020116 PNAS Latest Articles | 1of10 Downloaded by guest on October 1, 2021 A (OSGEP) is a commercial enzyme historically marketed as having mucin-degrading activity. Unfortunately, OSGEP’sapparentac- tivity has not been tied to a gene sequence that is amenable to recombinant expression, prompting the current view that OSGEP may act as a mixture of several unknown enzymes (29). The ubiquitous and highly conserved nature of mucin struc- tures implies an ecological need for enzymes with mucin-specific proteolytic activity. Indeed, recent evidence has pointed to the existence of families of mucin-targeting proteases comprising Mucinase cell cell hundreds of enzymes largely found in organisms living in mucin- rich host environments (30–32).Onesuchenzyme,secretedprotease B C Degly. mix of C1 esterase inhibitor (StcE), is a zinc metalloprotease of hu- man pathogenic enterohemorrhagic Escherichia coli (EHEC). rhMUC16PODXLCD43 PSGL1Syncam1CD45 BSA Fetuin Discovered by Welch and coworkers (33) and crystallized by StcE – +–+–+–+–+–+–+–+ – StcEE447DTrypsin– StcEE447DTrypsin Strynadka and coworkers (34), StcE promotes EHEC patho- 198 180 98 82 genesis in humans by cleaving the protective mucus layers of the 62 gut (35, 36). It is reported to cleave densely O-glycosylated 49 42 proteins, but not N-glycosylated or sparsely O-glycosylated sub- 38 strates (31). Given these reported pathogenic properties, we 28 17 18 speculated that StcE could be transformed into a research tool to 14 efficiently and selectively cleave human mucins. Mucin-specific proteolysis would be a valuable addition to the biochemist’s 6 toolbox, enabling mucin-domain glycoproteins to be selectively Fig. 1. StcE is a protease that selectively cleaves mucins. (A) A mucinase liberated from biological samples and cut into fragments ame- would enable mucin-domain glycoproteins to be selectively removed from nable to analysis (Fig. 1A, Right). biological samples and cut into fragments, facilitating their analysis. Cellular Here, we report that StcE has a distinct peptide- and glycan- and tissue experiments are depicted in Figs. 5 and 6. (B) Recombinant gly- based cleavage motif that enables high
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