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Sequence and conformational specificity in substrate recognition: several human Kunitz protease inhibitor domains are specific substrates of mesotrypsin.

Pendlebury D, Wang R, Henin RD, Hockla A, Soares AS, Madden BJ, Kazanov MD, Radisky ES
J Biol Chem 289 32783-97 (2014)
Cited: 26 times
EuropePMC logo PMID: 25301953

Abstract

Mesotrypsin is an isoform of trypsin that is uniquely resistant to polypeptide trypsin inhibitors and can cleave some inhibitors rapidly. Previous studies have shown that the amyloid precursor protein Kunitz protease inhibitor domain (APPI) is a specific substrate of mesotrypsin and that stabilization of the APPI cleavage site in a canonical conformation contributes to recognition by mesotrypsin. We hypothesized that other proteins possessing potential cleavage sites stabilized in a similar conformation might also be mesotrypsin substrates. Here we evaluated a series of candidate substrates, including human Kunitz protease inhibitor domains from amyloid precursor-like protein 2 (APLP2), bikunin, hepatocyte growth factor activator inhibitor type 2 (HAI2), tissue factor pathway inhibitor-1 (TFPI1), and tissue factor pathway inhibitor-2 (TFPI2), as well as E-selectin, an unrelated protein possessing a potential cleavage site displaying canonical conformation. We find that Kunitz domains within APLP2, bikunin, and HAI2 are cleaved by mesotrypsin with kinetic profiles of specific substrates. TFPI1 and TFPI2 Kunitz domains are cleaved less efficiently by mesotrypsin, and E-selectin is not cleaved at the anticipated site. Cocrystal structures of mesotrypsin with HAI2 and bikunin Kunitz domains reveal the mode of mesotrypsin interaction with its canonical substrates. Our data suggest that major determinants of mesotrypsin substrate specificity include sequence preferences at the P1 and P'2 positions along with conformational stabilization of the cleavage site in the canonical conformation. Mesotrypsin up-regulation has been implicated previously in cancer progression, and proteolytic clearance of Kunitz protease inhibitors offers potential mechanisms by which mesotrypsin may mediate pathological effects in cancer.

Reviews - 4u32 mentioned but not cited (1)

  1. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Shen LW, Mao HJ, Wu YL, Tanaka Y, Zhang W. Biochimie 142 1-10 (2017)

Articles - 4u32 mentioned but not cited (4)

  1. Sequence and conformational specificity in substrate recognition: several human Kunitz protease inhibitor domains are specific substrates of mesotrypsin. Pendlebury D, Wang R, Henin RD, Hockla A, Soares AS, Madden BJ, Kazanov MD, Radisky ES. J Biol Chem 289 32783-32797 (2014)
  2. Mesotrypsin Has Evolved Four Unique Residues to Cleave Trypsin Inhibitors as Substrates. Alloy AP, Kayode O, Wang R, Hockla A, Soares AS, Radisky ES. J Biol Chem 290 21523-21535 (2015)
  3. The Kunitz Domain I of Hepatocyte Growth Factor Activator Inhibitor-2 Inhibits Matriptase Activity and Invasive Ability of Human Prostate Cancer Cells. Wu SR, Teng CH, Tu YT, Ko CJ, Cheng TS, Lan SW, Lin HY, Lin HH, Tu HF, Hsiao PW, Huang HP, Chen CH, Lee MS. Sci Rep 7 15101 (2017)
  4. Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19. Bai X, Buckle AM, Vladar EK, Janoff EN, Khare R, Ordway D, Beckham D, Fornis LB, Majluf-Cruz A, Fugit RV, Freed BM, Kim S, Sandhaus RA, Chan ED. Sci Rep 12 5207 (2022)


Reviews citing this publication (3)

  1. The Inter-α-Trypsin Inhibitor Family: Versatile Molecules in Biology and Pathology. Lord MS, Melrose J, Day AJ, Whitelock JM. J Histochem Cytochem 68 907-927 (2020)
  2. The roles of proteases in prostate cancer. Koistinen H, Kovanen RM, Hollenberg MD, Dufour A, Radisky ES, Stenman UH, Batra J, Clements J, Hooper JD, Diamandis E, Schilling O, Rannikko A, Mirtti T. IUBMB Life 75 493-513 (2023)
  3. Extracellular proteolysis in cancer: Proteases, substrates, and mechanisms in tumor progression and metastasis. Radisky ES. J Biol Chem 300 107347 (2024)

Articles citing this publication (18)

  1. Epithelial expression and function of trypsin-3 in irritable bowel syndrome. Rolland-Fourcade C, Denadai-Souza A, Cirillo C, Lopez C, Jaramillo JO, Desormeaux C, Cenac N, Motta JP, Larauche M, Taché Y, Vanden Berghe P, Neunlist M, Coron E, Kirzin S, Portier G, Bonnet D, Alric L, Vanner S, Deraison C, Vergnolle N. Gut 66 1767-1778 (2017)
  2. Combinatorial protein engineering of proteolytically resistant mesotrypsin inhibitors as candidates for cancer therapy. Cohen I, Kayode O, Hockla A, Sankaran B, Radisky DC, Radisky ES, Papo N. Biochem J 473 1329-1341 (2016)
  3. An Acrobatic Substrate Metamorphosis Reveals a Requirement for Substrate Conformational Dynamics in Trypsin Proteolysis. Kayode O, Wang R, Pendlebury DF, Cohen I, Henin RD, Hockla A, Soares AS, Papo N, Caulfield TR, Radisky ES. J Biol Chem 291 26304-26319 (2016)
  4. SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase. Holt-Danborg L, Vodopiutz J, Nonboe AW, De Laffolie J, Skovbjerg S, Wolters VM, Müller T, Hetzer B, Querfurt A, Zimmer KP, Jensen JK, Entenmann A, Heinz-Erian P, Vogel LK, Janecke AR. Hum Mol Genet 28 828-841 (2019)
  5. HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase. Nonboe AW, Krigslund O, Soendergaard C, Skovbjerg S, Friis S, Andersen MN, Ellis V, Kawaguchi M, Kataoka H, Bugge TH, Vogel LK. Traffic 18 378-391 (2017)
  6. PRSS3/Mesotrypsin and kallikrein-related peptidase 5 are associated with poor prognosis and contribute to tumor cell invasion and growth in lung adenocarcinoma. Ma H, Hockla A, Mehner C, Coban M, Papo N, Radisky DC, Radisky ES. Sci Rep 9 1844 (2019)
  7. Mesotrypsin Signature Mutation in a Chymotrypsin C (CTRC) Variant Associated with Chronic Pancreatitis. Szabó A, Ludwig M, Hegyi E, Szépeová R, Witt H, Sahin-Tóth M. J Biol Chem 290 17282-17292 (2015)
  8. Climbing Up and Down Binding Landscapes through Deep Mutational Scanning of Three Homologous Protein-Protein Complexes. Heyne M, Shirian J, Cohen I, Peleg Y, Radisky ES, Papo N, Shifman JM. J Am Chem Soc 143 17261-17275 (2021)
  9. Disulfide engineering of human Kunitz-type serine protease inhibitors enhances proteolytic stability and target affinity toward mesotrypsin. Cohen I, Coban M, Shahar A, Sankaran B, Hockla A, Lacham S, Caulfield TR, Radisky ES, Papo N. J Biol Chem 294 5105-5120 (2019)
  10. Small molecule inhibitors of mesotrypsin from a structure-based docking screen. Kayode O, Huang Z, Soares AS, Caulfield TR, Dong Z, Bode AM, Radisky ES. PLoS One 12 e0176694 (2017)
  11. Inactivation of mesotrypsin by chymotrypsin C prevents trypsin inhibitor degradation. Toldi V, Szabó A, Sahin-Tóth M. J Biol Chem 295 3447-3455 (2020)
  12. Pre-equilibrium competitive library screening for tuning inhibitor association rate and specificity toward serine proteases. Cohen I, Naftaly S, Ben-Zeev E, Hockla A, Radisky ES, Papo N. Biochem J 475 1335-1352 (2018)
  13. KLK14 interactions with HAI-1 and HAI-2 serine protease inhibitors: A molecular dynamics and relative free-energy calculations study. Solís-Calero C, Carvalho HF. Cell Biol Int 41 1246-1264 (2017)
  14. Avidity observed between a bivalent inhibitor and an enzyme monomer with a single active site. Lacham-Hartman S, Shmidov Y, Radisky ES, Bitton R, Lukatsky DB, Papo N. PLoS One 16 e0249616 (2021)
  15. Mouse model suggests limited role for human mesotrypsin in pancreatitis. Mosztbacher D, Sahin-Tóth M. Pancreatology 21 342-352 (2021)
  16. Shear Stress Drives the Cleavage Activation of Protease-Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells. Zhou M, Li K, Luo KQ. Adv Sci (Weinh) 10 e2301059 (2023)
  17. Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes. Goettig P, Chen X, Harris JM. Int J Mol Sci 25 2429 (2024)
  18. Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers. Sananes A, Cohen I, Allon I, Ben-David O, Abu Shareb R, Yegodayev KM, Stepensky D, Elkabets M, Papo N. Mol Oncol 17 2337-2355 (2023)


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