Selective substrates and inhibitors for kallikrein-related peptidase 7 (KLK7) shed light on KLK proteolytic activity in the stratum corneum

de Veer, Simon J., Furio, Laetitia, Swedberg, Joakim E., Munro, Christopher A., Brattsand, Maria, Clements, Judith A., Hovnanian, Alain and Harris, Jonathan M. (2017) Selective substrates and inhibitors for kallikrein-related peptidase 7 (KLK7) shed light on KLK proteolytic activity in the stratum corneum. The Journal of Investigative Dermatology, 137 2: 430-439. doi:10.1016/j.jid.2016.09.017

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Author de Veer, Simon J.
Furio, Laetitia
Swedberg, Joakim E.
Munro, Christopher A.
Brattsand, Maria
Clements, Judith A.
Hovnanian, Alain
Harris, Jonathan M.
Title Selective substrates and inhibitors for kallikrein-related peptidase 7 (KLK7) shed light on KLK proteolytic activity in the stratum corneum
Journal name The Journal of Investigative Dermatology   Check publisher's open access policy
ISSN 1523-1747
0022-202X
Publication date 2017-02-01
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.jid.2016.09.017
Open Access Status File (Author Post-print)
Volume 137
Issue 2
Start page 430
End page 439
Total pages 10
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2017
Language eng
Formatted abstract
Proteases have pivotal roles in the skin's outermost layer, the epidermis. In the stratum corneum, serine proteases from the kallikrein-related peptidase (KLK) family have been implicated in several key homeostatic processes, including desquamation. However, the precise contribution of specific KLKs to each process remains unclear. To address this, we used a chemical biology approach and designed selective substrates and inhibitors for KLK7, the most abundant KLK protease in the stratum corneum. The resulting KLK7 inhibitor is the most potent inhibitor of this protease reported to date (Ki = 140 pM), and displays at least 1,000-fold selectivity over several proteases that are related by function (KLK5 and KLK14) or specificity (chymotrypsin). We then used substrates and inhibitors for KLK5, KLK7, and KLK14 to explore the activity of each protease in the stratum corneum using casein zymography and an ex vivo desquamation assay. These experiments provide the most detailed assessment of each KLK's contribution to corneocyte shedding in the plantar stratum corneum, revealing that inhibition of KLK7 alone is sufficient to block shedding, whereas KLK5 is also a major contributor. Collectively, these findings unveil chemical tools for studying KLK activity and demonstrate their potential for characterizing KLK biological functions in epidermal homeostasis.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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