THE CRYSTAL-STRUCTURE OF BOVINE BILE-SALT ACTIVATED LIPASE - INSIGHTSINTO THE BILE-SALT ACTIVATION MECHANISM

Background: The intestinally located pancreatic enzyme, bile salt acti vated lipase (BAL), possesses unique activities for digesting differen t kinds of lipids. It also differs from other lipases in a requirement of bile salts for activity. A structure-based explanation for these u nique properties has not been reached so far due to the absence of a t hree-dimensional structure. Results: The crystal structures of bovine BAL and its complex with taurocholate have been determined at 2.8 Angs trom resolution. The overall structure of BAL belongs to the alpha/bet a hydrolase fold family. Two bile salt binding sites were found in eac h BAL molecule within the BAL-taurocholate complex structure. One of t hese sites is located close to a hairpin loop near the active site. Up on the binding of taurocholate, this loop becomes less mobile and assu mes a different conformation. The other bile salt binding site is loca ted remote from the active site. In both structures, BAL forms similar dimers with the active sites facing each other. Conclusions: Bile sal ts activate BAL by binding to a relatively short ten-residue loop near the active site, and stabilize the loop in an open conformation. Pres umably, this conformational change leads to the formation of the subst rate-binding site, as suggested from kinetic data. The BAL dimer obser ved in the crystal structure may also play a functional role under phy siological conditions.