The insulin receptor is functionally important for negative cooperativity, down-regulation, and beta-subunit tyrosine kinase activity. There are two recognized epitopes of the alpha-subunit. One epitope is close to the insulin-binding site and plays a role in insulin-induced negative cooperativity and down-regulation. The other site (recognized by the monoclonal MA-20 antibody) is at a distance from the insulin-binding site, where it only plays a role in down-regulation. Both epitopes appear to be independent of insulin receptor tyrosine kinase activity.