Structural and mechanistic principles of intramembrane proteolysis – lessons from rhomboids

• Published in: The FEBS journal 2013-04, Vol.280 (7), p.1579-1603
• Main Author: Strisovsky, Kvido
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Aspartic Acid Proteases - chemistry; Aspartic Acid Proteases - metabolism; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Biochemistry; Catalytic Domain; Crystal structure; DNA-Binding Proteins - chemistry; Drosophila Proteins - chemistry; Drosophila Proteins - metabolism; Endopeptidases - chemistry; Endopeptidases - metabolism; enzymatic mechanism; Escherichia coli Proteins - chemistry; Evolution, Molecular; intramembrane protease; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Membranes; Metalloendopeptidases - chemistry; Metalloendopeptidases - metabolism; Molecular Sequence Data; presenilin; Presenilins - chemistry; Presenilins - metabolism; Prokaryotes; Proteases; Protein Conformation; Proteolysis; rhomboid; Serine Proteases - chemistry; Serine Proteases - metabolism; signal peptide peptidase; site‐2 protease; Substrate Specificity; γ‐secretase
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.12199

Intramembrane proteases cleave membrane proteins in their transmembrane helices to regulate a wide range of biological processes. They catalyse hydrolytic reactions within the hydrophobic environment of lipid membranes where water is normally excluded. How? Do the different classes of intramembrane proteases share any mechanistic principles? In this review these questions will be discussed in view of the crystal structures of prokaryotic members of the three known catalytic types of intramembrane proteases published over the past 7 years. Rhomboids, the intramembrane serine proteases that are the best understood family, will be the initial area of focus, and the principles that have arisen from a number of structural and biochemical studies will be considered. The site‐2 metalloprotease and GXGD‐type aspartyl protease structures will then be discussed, with parallels drawn and differences highlighted between these enzymes and the rhomboids. Despite the significant advances achieved so far, to obtain a detailed understanding of the mechanism of any intramembrane protease, high‐resolution structural information on the substrate–enzyme complex is required. This remains a major challenge for the field. Intramembrane proteases regulate a wide range of biological processes, but their mechanisms are unclear. In this review I discuss the available crystal structures of prokaryotic homologs of all three classes of intramembrane proteases: the rhomboids, the intramembrane aspartyl proteases and metalloproteases, and review our current understanding of their catalytic properties.