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Research J. Michael Engle

Domain diagram of a generic ADAMTS proteinase:

  1. Signal Domain Like most secreted proteins the ADAMTS proteinases contain a signal domain. This small stretch of basic amino acids is the signal to the cell that this protein should be secreted from the cell.
  2. Pro Domain The pro domain is quite long in the ADAMTS proteinases (except for ADAMTS-13). Within each pro domain is a cysteine amino acid which chelates with the zinc ion in the active site. This chelation with the zinc ion renders the proteinase inactive. In order to active an ADAMTS proteinase the pro region is cleaved off by another proteinase. This removes the cysteine chelation of the active site zinc ion. For the ADAMTS proteinases the cleavage of the pro domain is accomplished by the proteinase furin. Furin is found in the golgi apparatus and cleaves at the consensus sequence RXXR. Thus ADAMTS proteinases are secreted as active proteinases.
  3. Catalytic Domain This area of the protein contains the active site, which is responsible for actually cutting the substrate. This site binds a Zinc molecule which participates in hydrolysing the substrate protein. The ADAMTS zinc binding amino acid signature is HEXXHXXGXXHD where X is almost any amino acid. After the zinc binding region a Methionine amino acid is found. This constitutes the Met-turn which causes the protein to exhibit a sharp right handed turn.
  4. Disintegrin-like Domain This domain exhibits similarity to snake venom disintegrins. But the function of this domain remains to be elucidated.
  5. The TSP Like domain is similar in sequence to the type 1 repeat of thrombospondins 1 and 2. This (the first) of the TSR like domains is the most homologous among the ADAMTS proteinases.
  6. CYS Rich stands for cysteine rich domain. This area of the protein contains many cysteine amino acids. Most ADAMTS proteinases contain ten cysteine residues in this area and their location is quite similar among the ADAMTS proteinases.
  7. Spacer The spacer domain does not contain any cysteine amino acids at all. The length is quite variable among the ADAMTS proteinases. Recent research suggests that the ADAMTS proteinases must be cut in this region in order to achieve their maximal catalytic activity.
  8. TSP Like As you can see from the figure most ADAMTS proteinases contain more TSP Like domains near their C terminus. The exception is ADAMTS-4 which contains only the first TSP Like domain. These additional TSP Like domains vary in the number that are in ADAMTS proteinases and some may even be separated by long non-TSP Like sequences. Finally these terminal TSP Like domains are not nearly as homologous as the first TSP Like domain.
  9. C terminal domains Some of the ADAMTS proteinases contain an additional C terminal domain. These vary from one molecule to another. Some of the domains reveal homology to other domains like: the PLAC domain, the CUB domain, and a GON-1 domain.