Intramembrane Proteolysis

Abstract

Evolutionarily conserved membrane‐embedded enzymes somehow use water to hydrolyze peptide bonds that reside within the lipid bilayer. These proteases are stitched into the membrane and bear little or no sequence similarity to other known proteases with one exception: All known intramembrane proteases apparently have converged on catalytic mechanisms that resemble those of proteases that reside in the aqueous milieu. The identities of these residues suggest that the intramembrane proteases use catalytic functionalities similar to those found in their soluble counterparts. However, in contrast to classical proteases, residues essential for catalysis lie within predicted hydrophobic transmembrane domains. Current research is focused on elucidating the range of biologic roles of these proteases, identifying their substrates, and understanding their structure and mechanism of action. Such knowledge is important because the intramembrane proteases discovered thus far play critical regulatory roles in biology and contribute to human disease.

Mechanisms of peptide and phosphoester hydrolysis catalyzed by two promiscuous metalloenzymes (insulin degrading enzyme and glycerophosphodiesterase) and their synthetic analogues

“…18,19 To catalytically hydrolyze these bonds, nature has designed specific enzymes that contain both metallic and non-metallic active sites. [20][21][22][23][24][25][26] Among them, mono-or binuclear metal center possessing enzymes are known as metallohydrolases. [3][4][5]10,[24][25][26][27][28][29][30] The occurrence of the metal ion(s) (Mg, Zn, Mn, Ca, or Fe) in these enzymes depends on its biological availability and chemically relevant properties such as high Lewis acidity, strong nucleophilicity, rapid ligand exchange rate and redox inertness.…”

“…In contrast, the interactions between Aβ and IDE were mainly composed of direct hydrogen bonds and π-π stacking. The number of direct hydrogen bonds [17][18][19][20][21][22][23][24][25][26][27][28][29][30] formed within IDE was approximately four times higher than those [3][4][5][6][7][8] formed by HSA. The binding of I P to HSA did not alter the overall structure of HSA, which was dominated by α helical conformation (67%).…”