The Metalloprotease Disintegrin ADAM8

By Uwe Schlomann, D. Wildeboer, A. Webster, O. Antropova, D. Zeuschner, C. Graham Knight, Andrew J. P. Docherty, M. Lambert, L. Skelton, H. Jockusch and 1 more. 2002

130 citations recorded by the source corpus.

ADAMs (a disintegrinand metalloprotease domains) are metalloprotease and disintegrin domain-containing transmembrane glycoproteins with proteolytic, cell adhesion, cell fusion, and cell signaling properties. ADAM8 was originally cloned from monocytic cells, and its distinct expression pattern indicates possible roles in both immunology and neuropathology. Here we describe our analysis of its biochemical properties. In transfected COS-7 cells, ADAM8 is localized to the plasma membrane and processed into two forms derived either by prodomain removal or as remnant protein comprising the extracellular region with the disintegrin domain at the N terminus. Proteolytic removal of the ADAM8 propeptide was completely blocked in mutant ADAM8 with a Glu330 to Gln exchange (EQ-A8) in the Zn2+ binding motif (HE330LGHNLGMSHD), arguing for autocatalytic prodomain removal. In co-transfection experiments, the ectodomain but not the entire MP domain of ADAM8 was able to remove the prodomain from EQ-ADAM8. With cells expressing ADAM8, cell adhesion to a substrate-bound recombinant ADAM8 disintegrin/Cys-rich domain was observed in the absence of serum, blocked by an antibody directed against the ADAM8 disintegrin domain. Soluble ADAM8 protease, consisting of either the metalloprotease domain or the complete ectodomain, cleaved myelin basic protein and a fluorogenic peptide substrate, and was inhibited by batimastat (BB-94, IC50∼50 nm) but not by recombinant tissue inhibitor of matrix metalloproteinases 1, 2, 3, and 4. Our findings demonstrate that ADAM8 processing by autocatalysis leads to a potential sheddase and to a form of ADAM8 with a function in cell adhesion.

Subfields: Immunology and Allergy, Molecular Biology, Oncology

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In Immunology and Allergy

1. C. Blobel
2. S. Zhong
3. R. Khalil

In Molecular Biology

1. C. Blobel
2. R. Khalil
3. S. Zhong
4. D. Edwards
5. M. Handsley
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In Oncology

1. S. Zhong
2. C. Blobel
3. R. Khalil
4. D. Edwards
5. M. Handsley
6. C. Pennington

Citations in the corpus

• A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “some ADAMs auto-catalytically remove the pro-domain in order to complete their transformation from inactive pro-protein to active protein, and proceed to the following activation process [31].”
• The ADAM metalloproteinases (2008, background): “Moreover for at least two ADAMs (ADAM-8 and -28) there is evidence from analysis of inactive E-A mutations in the Zn-binding site for autocatalytic removal of the pro-domain (Howard et al., 2000; Schlomann et al., 2002).”
• Metalloprotease‐disintegrin ADAM8: Expression analysis and targeted deletion in mice (2005, background): “The tissue inhibitor of matrix metalloproteinases (TIMP) -inhibitor profile of ADAM8 is like that of ADAM9 in that it is not inhibited by any of the known TIMP proteins (Amour et al., 2002; Schlomann et al., 2002).”
• The ADAMs family of metalloproteases: multidomain proteins with multiple functions. (2003, background): “This is most clearly shown with ADAM8 and ADAM28, in which activity-blocking mutations in the metallopro- tease domains produces only the precursor form of the protein in transfected cells (Howard et al. 2000; Schlomann et al. 2002).”