Structural and functional evidence for a substrate exclusion mechanism in mammalian tolloid like-1 (TLL-1) proteinase

Berry, Richard; Jowitt, Thomas A.; Garrigue-Antar, Laure; Kadler, Karl E.; Baldock, Clair

doi:10.1016/j.febslet.2009.12.050

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Volume 584, Issue 4 , Pages 657-661, 19 February 2010

Structural and functional evidence for a substrate exclusion mechanism in mammalian tolloid like-1 (TLL-1) proteinase

Edited by Zhijie Chang

Richard Berry
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Manchester M13 9PT, UK
Thomas A. Jowitt
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Manchester M13 9PT, UK
Laure Garrigue-Antar
- Laboratoire CRRET/UMR CNRS 7149, Facultė des Sciences, Universitė Paris-Est Crėteil Val de Marne (UPEC), 94010 CRETEIL Cedex, France
Karl E. Kadler
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Manchester M13 9PT, UK
Clair Baldock
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Manchester M13 9PT, UK
- Corresponding author. Fax: +44 161 2755082.

Received 1 October 2009; received in revised form 10 December 2009; accepted 19 December 2009. published online 29 December 2009.

Abstract

Bone morphogenetic protein-1 (BMP-1)/tolloid proteinases are fundamental to regulating dorsal ventral patterning and extracellular matrix deposition. In mammals there are four proteinases, the splice variants BMP-1 and mammalian tolloid (mTLD), and tolloid like-1 and -2 (TLL-1/2). BMP-1 has the highest catalytic activity and lacks three non-catalytic domains. We demonstrate that TLL-1, which has intermediate activity, forms a calcium-ion dependent dimer with monomers stacked side-by-side. In contrast, truncated TLL-1 molecules having the same shorter structure as BMP-1 are monomers and have improved activity towards their substrate chordin. The increased activity exceeds not only that of full-length TLL-1 but also BMP-1.