Structure-Function Analyses of Human Kallikrein-related Peptidase 2 Establish the 99-Loop as Master Regulator of Activity

Skala, Wolfgang; Utzschneider, Daniel T.; Magdolen, Viktor; Debela, Mekdes; Guo, Songjun; Craik, Charles S.; Brandstetter, Hans; Goettig, Peter

doi:10.1074/jbc.m114.598201

Cited by 29 publications

(54 citation statements)

References 101 publications

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“…In this state, the enzyme pocket is always available to recognize and accommodate a substrate. However, the substrate is not degraded because the catalytic triad is not properly aligned …”

Section: Physiological Inhibitorsmentioning

confidence: 95%

Inhibitors of kallikrein‐related peptidases: An overview

Masurier

Arama

Amri

et al. 2017

Medicinal Research Reviews

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Kallikrein-related peptidases (KLKs) are a family of 15 secreted serine proteases that are involved in various physiological processes. Their activities are subtly regulated by various endogenous inhibitors, ranging from metallic ions to macromolecular entities such as proteins. Furthermore, dysregulation of KLK activity has been linked to several pathologies, including cancer and skin and inflammatory diseases, explaining the numerous efforts to develop KLK-specific pharmacological inhibitors as potential therapeutic agents. In this review, we focus on the huge repertoire of KLKs inhibitors reported to date with a special emphasis on the diversity of their molecular mechanisms of inhibition.

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“…In this state, the enzyme pocket is always available to recognize and accommodate a substrate. However, the substrate is not degraded because the catalytic triad is not properly aligned …”

Section: Physiological Inhibitorsmentioning

confidence: 95%

Inhibitors of kallikrein‐related peptidases: An overview

Masurier

Arama

Amri

et al. 2017

Medicinal Research Reviews

View full text Add to dashboard Cite

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“…1E). Because of the loop location close to Asp102 (chymotrypsin numbering), this fragment is postulated to be involved in interacting with substrates, as confirmed by structural and mutational studies of KLK2 [3]. The other six surface loops of kallikreins that surround the active site display high variability and may therefore contribute to differences in substrate specificities among kallikreins.…”

Section: Kallikreins As Proteases: Basic Informationmentioning

confidence: 98%

“…The zinc cation interacts with salt bridges formed in active sites of KLK4 [10], KLK5 [11], and KLK7 [12], or modifies the kallikrein loop in KLK2 [3]. …”

Section: Kallikreins As Proteases: Basic Informationmentioning

confidence: 99%

Kallikreins – The melting pot of activity and function

et al. 2016

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The human tissue kallikrein and kallikrein-related peptidases (KLKs), encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. Because of the broad spectrum of processes that are modulated by kallikreins, these proteases are the subject of extensive investigations. This review brings together basic information about the biochemical properties affecting enzymatic activity, with highlights on post-translational modifications, especially glycosylation. Additionally, we present the current state of knowledge regarding the physiological functions of KLKs in major human organs and outline recent discoveries pertinent to the involvement of kallikreins in cell signaling and in viral infections. Despite the current depth of knowledge of these enzymes, many questions regarding the roles of kallikreins in health and disease remain unanswered.

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“…This effect could be explained with an influence of the core glycan (GlcNAc 2 Man 3 ) at Asn95 in the 99-loop close to the active site, favoring the formation of a type I β-turn over the Asx turn of glycan-free KLK2 [153,154]. Apparently, the flexible 99-loop is wide open in the glycan-free KLK2 crystal structure, whereas it may adopt a closed conformation due to the presence of the N -glycan, as in the related KLK1 structure (Figure 3G) [155,156]. The open loop allows for rapid binding of the substrate in the non-prime region at the specificity pockets S4 to S2, which can be explained by a higher k on rate, resulting in a lower K M = ( k off + k cat )/ k on .…”

Section: Effects Of Glycosylation On Proteasesmentioning

confidence: 99%

“…Similarly, the presence of the N -glycan in the 99-loop of KLK2 appears to regulate the substrate turnover by favoring the closed state (E) over the open E* state, as proposed by the conformational selection model, which is opposed to the induced fit model [155,160]. Thorough analyses of these two mechanistic principles conclude with the combined view of induced fit and conformational selection as extremes of one flux model [161,162].…”

Section: Effects Of Glycosylation On Proteasesmentioning

confidence: 99%

Effects of Glycosylation on the Enzymatic Activity and Mechanisms of Proteases

Goettig

2016

IJMS

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Posttranslational modifications are an important feature of most proteases in higher organisms, such as the conversion of inactive zymogens into active proteases. To date, little information is available on the role of glycosylation and functional implications for secreted proteases. Besides a stabilizing effect and protection against proteolysis, several proteases show a significant influence of glycosylation on the catalytic activity. Glycans can alter the substrate recognition, the specificity and binding affinity, as well as the turnover rates. However, there is currently no known general pattern, since glycosylation can have both stimulating and inhibiting effects on activity. Thus, a comparative analysis of individual cases with sufficient enzyme kinetic and structural data is a first approach to describe mechanistic principles that govern the effects of glycosylation on the function of proteases. The understanding of glycan functions becomes highly significant in proteomic and glycomic studies, which demonstrated that cancer-associated proteases, such as kallikrein-related peptidase 3, exhibit strongly altered glycosylation patterns in pathological cases. Such findings can contribute to a variety of future biomedical applications.

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Structure-Function Analyses of Human Kallikrein-related Peptidase 2 Establish the 99-Loop as Master Regulator of Activity

Cited by 29 publications

References 101 publications

Inhibitors of kallikrein‐related peptidases: An overview

Inhibitors of kallikrein‐related peptidases: An overview

Kallikreins – The melting pot of activity and function

Effects of Glycosylation on the Enzymatic Activity and Mechanisms of Proteases

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