The cysteine-rich domain regulates ADAM protease function in vivo

By Katherine Smith, Alban Gaultier, Hélène Cousin, D. Alfandari, J. White, D. DeSimone. 2002

124 citations recorded by the source corpus.

ADAMs are membrane-anchored proteases that regulate cell behavior by proteolytically modifying the cell surface and ECM. Like other membrane-anchored proteases, ADAMs contain candidate “adhesive” domains downstream of their metalloprotease domains. The mechanism by which membrane-anchored cell surface proteases utilize these putative adhesive domains to regulate protease function in vivo is not well understood. We address this important question by analyzing the relative contributions of downstream extracellular domains (disintegrin, cysteine rich, and EGF-like repeat) of the ADAM13 metalloprotease during Xenopus laevis development. When expressed in embryos, ADAM13 induces hyperplasia of the cement gland, whereas ADAM10 does not. Using chimeric constructs, we find that the metalloprotease domain of ADAM10 can substitute for that of ADAM13, but that specificity for cement gland expansion requires a downstream extracellular domain of ADAM13. Analysis of finer resolution chimeras indicates an essential role for the cysteine-rich domain and a supporting role for the disintegrin domain. These and other results reveal that the cysteine-rich domain of ADAM13 cooperates intramolecularly with the ADAM13 metalloprotease domain to regulate its function in vivo. Our findings thus provide the first evidence that a downstream extracellular adhesive domain plays an active role in regulating ADAM protease function in vivo. These findings are likely relevant to other membrane-anchored cell surface proteases.

Subfields: Immunology and Allergy, Oncology

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Citations in the corpus

A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “The C-domain of ADAM-13 is closely related to cell fixation, and can bind to the basement membrane proteins laminin and fibronectin [24].”
ADAMs family and relatives in cardiovascular physiology and pathology. (2016, background): “the basement membrane proteins laminin and fibronectin [18].”
Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C‐shaped scaffold (2006, unknown): “ADAM33 has been genetically linked with asthma (Van Eerdewegh et al, 2002).”
ADAMs: key components in EGFR signalling and development (2005, background): “The disintegrin domain and cysteine-rich region can also have a role in substrate targetin”
The ADAM metalloproteinases (2008, background): “In Xenopus laevis the metalloproteinase activity of ADAM-13 is required for cranial neural crest cell migration (Alfandari et al., 2001) , and when ADAM-13 is over-expressed in embryos it leads to hyperplasia of the cement gland (Smith et al., 2002) .”