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Characterization of...
Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis
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- Brännström, Kristoffer (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Öhman, Anders (author)
- Umeå universitet,Kemiska institutionen
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- von Pawel-Rammingen, Ulrich (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)
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- Olofsson, Anders (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Brattsand, Maria (author)
- Umeå universitet,Dermatologi och venereologi
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(creator_code:org_t)
- 2012-05-01
- 2012
- English.
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In: Biological chemistry (Print). - : Walter de Gruyter. - 1431-6730 .- 1437-4315. ; 393:5, s. 369-377
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- SPINK9, a Kazal-type serine protease inhibitor, is almost exclusively expressed in the palmo-plantar epidermis. SPINK9 selectively inhibits kallikrein-related peptidase 5 (KLK5), no other target enzyme is known at present. In this study, we defined the reactive loop to residues 48 and 49 of SPINK9 and characterized the inhibition and binding of different SPINK9 variants towards KLK5, KLK7, KLK8 and KLK14. Substitutions of single amino acids in the reactive loop had a large impact on both inhibitory efficiency and specificity. Binding studies showed that it is mainly the dissociation rate that is affected by the amino acid substitutions. The inhibitory effect of wild-type SPINK9 was clearly pH-dependent with an improved effect at a pH similar to that of the outer layers of the skin. Modeling of the enzyme-inhibitor complexes showed that the reactive loop of SPINK9 fits very well into the deep negatively charged binding pocket of KLK5. A decrease in pH protonates His48 of the wild-type protein resulting in a positively charged residue, thereby explaining the observed decreased dissociation rate. Interestingly, substitution with a positively charged amino acid at position 48 resulted in a more efficient inhibitor at higher pH.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- binding studies
- inhibition
- kallikrein-related peptidases
- Kazal-type inhibitor
- KLK5
- SPINK9
Publication and Content Type
- ref (subject category)
- art (subject category)
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