Structural Basis of the Zinc Inhibition of Human Tissue Kallikrein 5

Debela, Mekdes; Goettig, Peter; Magdolen, Viktor; Huber, Robert; Schechter, Norman M.; Bode, Wolfram

doi:10.1016/j.jmb.2007.08.042

Cited by 78 publications

(63 citation statements)

References 54 publications

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“…way, along with the sensitivity of these proteases to serpinor Kazal-type inhibitors, and to divalent ions (Borgono and Diamandis, 2004;Debela et al, 2006aDebela et al, , 2007. In contrast to the well-known coagulation cascade that consists of sequential proteolytic activations, KLKs seem to be rather integrated within a proteolytic network which involves a large array of (pro-)proteases, with no clear hierarchy.…”

Section: Discussionmentioning

confidence: 99%

Interdependence of kallikrein-related peptidases in proteolytic networks

Beaufort

Płaza²,

Utzschneider

et al. 2010

Biological Chemistry

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Human kallikrein-related peptidases (KLKs) are 15 homologous serine proteases involved in several (patho)physiological processes, including cancer. Secreted as precursors, they are activated upon proteolytic release of a short propeptide. We searched for interconnection of KLKs within extracellular proteolytic networks leading to activation of protease zymogens and found that (i) pro-KLK activation by other KLKs is scarce, with the exception of pro-KLK11, which is efficiently activated by KLK4 and 5; (ii) pro-KLK4 is activated by matrix metalloproteinase 3; and (iii) trypsinlike KLKs efficiently activate the serine protease urokinase. Our observations provide new insights into the regulation of these important tumor-associated proteases.

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Section: Discussionmentioning

confidence: 99%

Interdependence of kallikrein-related peptidases in proteolytic networks

Beaufort

Płaza²,

Utzschneider

et al. 2010

Biological Chemistry

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“…Yeast-expressed KLK5 appeared to be glycosylated with molecular masses from 30 to 44 kDa, which turned over tryptic substrates like VPR-AMC; PNGase F treatment reduced the mass to 26 or 28 kDa, respectively Michael et al, 2005). The two GlcNAc residues that are well defined in the electron density in the insect cell-expressed KLK5 crystal structure are located in a solvent exposed region of a β-sheet distant from the active site, similar to the three other potential sites (2PSX, Figure 3) (Mekdes Debela et al, 2007a).…”

Section: The Epidermal Klks 5 7 and 14mentioning

confidence: 91%

Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity

Guo

Skala

Magdolen

et al. 2014

Biological Chemistry

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Most kallikrein-related peptidases (KLKs) are N-glycosylated with N-acetylglucosamine 2 -mannose 9 units at Asn-Xaa-Ser/Thr sequons during protein synthesis and translocation into the endoplasmic reticulum. These N-glycans are modified in the Golgi machinery, where additional O-glycosylation at Ser and Thr takes place, before exocytotic release of the KLKs into the extracellular space. Sequons are present in all 15 members of the KLKs and comparative studies for KLKs from natural and recombinant sources elucidated some aspects of glycosylation. Although glycosylation of mammalian KLKs 1, 3, 4, 6, and 8 has been analyzed in great detail, e.g., by crystal structures, the respective function remains largely unclear. In some cases, altered enzymatic activity was observed for KLKs upon glycosylation. Remarkably, for KLK3/PSA, changes in the glycosylation pattern were observed in samples of benign prostatic hyperplasia and prostate cancer with respect to healthy individuals. Potential functions of KLK glycosylation in structural stabilization, protection against degradation, and activity modulation of substrate specificity can be deduced from a comparison with other glycosylated proteins and their regulation. According to the new concept of protein sectors, glycosylation distant from the active site might significantly influence the activity of proteases. Novel pharmacological approaches can exploit engineered glycans in the therapeutical context.

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“…Moreover, Zn 2+ inhibits KLK5 (Debela et al 2007). This might have clinical consequences, when Zink levels are low as in acrodermatits enteropathica.…”

Section: Other Regulating Factors Of Protease Activitymentioning

confidence: 97%

Epidermal Serine Proteases and Their Inhibitors in Atopic Dermatitis

Meyer‐Hoffert¹

2012

Atopic Dermatitis - Disease Etiology and Clinical Management

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Structural Basis of the Zinc Inhibition of Human Tissue Kallikrein 5

Cited by 78 publications

References 54 publications

Interdependence of kallikrein-related peptidases in proteolytic networks

Interdependence of kallikrein-related peptidases in proteolytic networks

Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity

Epidermal Serine Proteases and Their Inhibitors in Atopic Dermatitis

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