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Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
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2012 (engelsk)Inngår i: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 393, nr 5, s. 369-377Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
Walter de Gruyter, 2012. Vol. 393, nr 5, s. 369-377
Emneord [en]
binding studies, inhibition, kallikrein-related peptidases, Kazal-type inhibitor, KLK5, SPINK9
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Identifikatorer
URN: urn:nbn:se:umu:diva-56422DOI: 10.1515/hsz-2011-0238ISI: 000304334100007OAI: oai:DiVA.org:umu-56422DiVA, id: diva2:535013
Tilgjengelig fra: 2012-06-19 Laget: 2012-06-18 Sist oppdatert: 2018-06-08bibliografisk kontrollert

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Brännström, KristofferÖhman, Andersvon Pawel-Rammingen, UlrichOlofsson, AndersBrattsand, Maria

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