Intramembrane-cleaving Proteases

Michael S Wolfe

doi:10.1074/jbc.r800039200

Abstract

In the past decade or so, membrane-embedded proteases that carry out hydrolysis on the transmembrane region of their substrates have been discovered. These I-CLiPs2 (1) somehow create an environment for water and the hydrophilic residues needed for catalysis and bend or unwind their helical substrates to make the amide bonds susceptible to hydrolysis. Despite the distinction of being membrane-embedded and cleaving TMDs, the residues essential for catalysis by these I-CLiPs are virtually the same as those found in aqueous proteases, clear examples of convergent evolution toward a common mechanism. Described herein are the different types of I-CLiPs and an update on their structural and mechanistic features and biological roles.

Highlights

SREBPs are transcription factors that promote expression of genes involved in the synthesis of cholesterol and fatty acids
SREBPs are synthesized as a two-TMD precursor protein (Fig. 1A) that undergoes proteolytic release
The two histidines and the glutamate are required for S2P activity, consistent with known metalloprotease biochemistry in which the two histidines coordinate with zinc, the zinc activates the scissile amide bond, and the glutamate activates the catalytic water

Summary

Introduction

SREBPs are transcription factors that promote expression of genes involved in the synthesis of cholesterol and fatty acids (reviewed in Ref. 2). Mutation of the aminopeptidase domain was reported to prevent this interaction, suggesting that nicastrin is a gatekeeper for the ␥-secretase complex: type I membrane proteins that have not shed their ectodomains cannot interact properly with nicastrin and do not gain access to the active site.

Results

Conclusion