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Probing the Active Sites and Mechanisms of Rat Metalloproteases Meprin A and B
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G. P. Bertenshaw
Published/Copyright:
June 1, 2005
Abstract
Meprin A and B are highly regulated, secreted and cellsurface homo and heterooligomeric enzymes. Meprins are abundantly expressed in kidney and intestine. The multidomain α and β subunits have high sequence identity, however they have very different substrate specificities, oligomerization potentials and are differentially regulated. Here we describe that meprin subunit activities are modulated differently by physicochemical factors. Homooligomeric meprin B had an acidic pH optimum. The low pH protonation indicated the existence of at least two ionizable groups. An additional ionizable group generated a shoulder in the basic pH range. Homooligomeric meprin A had a neutral pH optimum and the activity curve revealed that two ionizable groups might be protonated at acidic pH similar to meprin B. Increasing the concentration of salt generally inhibited meprin B activity. Meprin A was inhibited at low salt concentrations but activated as salt was increased. This work has important implications in the elucidation of the catalytic mechanisms of meprins and other metalloproteases. In addition, the activity of meprin oligomers that arise in tissues will be affected by variations in pH and NaCl. This could have profound implications because meprins are exposed to a range of conditions in the extracellular milieu of renal and intestinal tissues and in inflammation and cancer.
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Published Online: 2005-06-01
Published in Print: 2002-08-27
Copyright © 2002 by Walter de Gruyter GmbH & Co. KG
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- Phage Display Substrate: A Blind Method for Determining Protease Specificity
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