Cleavage of the ADAMTS13 Propeptide Is Not Required for Protease Activity*

By Elaine M. Majerus, Xinglong Zheng, E. Tuley, J. Sadler. 2003

128 citations recorded by the source corpus.

ADAMTS13 belongs to the “a disintegrin and metalloprotease with thrombospondin repeats” family, and cleaves von Willebrand factor multimers into smaller forms. For several related proteases, normal folding and enzymatic latency depend on an NH2-terminal propeptide that is removed by proteolytic processing during biosynthesis. However, the ADAMTS13 propeptide is unusually short and poorly conserved, suggesting it may not perform these functions. ADAMTS13 was secreted from transfected HeLa cells with a half-time of 7 h and the rate-limiting step was exported from the endoplasmic reticulum. Deletion of the propeptide did not impair the secretion of active ADAMTS13, indicating that the propeptide is dispensable for folding. Furin was shown to be sufficient for ADAMTS13 propeptide processing in two ways. First, mutation of the furin consensus recognition site prevented propeptide cleavage in HeLa cells and resulted in secretion of pro-ADAMTS13. Second, furin-deficient LoVo cells secreted ADAMTS13 with the propeptide intact, and cotransfection with furin restored propeptide cleavage. In both cell lines, secreted pro-ADAMTS13 had normal proteolytic activity toward von Willebrand factor. In cells coexpressing both ADAMTS13 and von Willebrand factor, pro-ADAMTS13 cleaved pro-von Willebrand factor intracellularly. Therefore, the ADAMTS13 propeptide is not required for folding or secretion, and does not perform the common function of maintaining enzyme latency.

Subfields: Hematology, Immunology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Hematology

1. S. Zhong
2. R. Khalil
3. D. Edwards

In Immunology

1. S. Zhong
2. R. Khalil
3. S. Takeda

Citations in the corpus

• A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “ADAMTS-13 has an unusually short propeptide, and ADAMTS-9 and ADAMTS-13 zymogens appear to be active despite retention of the propeptide [39, 40].”
• The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family (2015, background): “This enzyme has an unusually short pro-domain that probably acts by influencing binding to other proteins or by regulating catalytic activity in some other way [22].”
• ADAM and ADAMTS Family Proteins and Snake Venom Metalloproteinases: A Structural Overview (2016, background): “Unlike other M12B members, the pro domain of ADAMTS13 is relatively short (only 41 residues) and is not required for its secretion and function [63].”
• ADAMs family and relatives in cardiovascular physiology and pathology. (2016, background): “The pro-domain in ADAMTSs is unusually short, and as they lack the cysteine switch that controls activation of MMPs, their pro-domain is believed to be involved in binding to other proteins or in regulating catalytic activity in otherways [108].”