The presenilins and signal peptide peptidase-like family, which are intramembrane aspartyl proteases, cleave substrates that include the Notch receptor and the amyloid precursor protein, which is implicated in Alzheimer's disease.

Rhomboids were first named after a mutation in the fruit fly Drosophila, discovered in a famous genetic screen that led to a Nobel Prize for Christiane Nüsslein-Volhard and Eric Wieschaus.

The structures also explained how a proteolytic reaction, which requires water molecules, can occur in the hydrophobic environment of a lipid bilayer: one of the central mysteries of intramembrane proteases.

[37][38][40][43][44] This notion is also supported by the fact that mutations in TMS 5 have only a marginal effect on the thermodynamic stability of rhomboid, unlike other regions of the molecule.

Some authors propose that substrate access involves a large lateral displacement movement of TMS 5 to open up the core of rhomboid.

Initial work indicated that rhomboids recognise instability of the transmembrane alpha-helix at the site of cleavage as the main substrate determinant.

[52] More recently, it has been found that rhomboid substrates are defined by two separable elements: the transmembrane domain and a primary sequence motif in or immediately adjacent to it.

[48] A detailed enzyme kinetics analysis has in fact shown that the recognition motif interactions with rhomboid active site determine the kcat of substrate cleavage.

[55] As a first step towards this goal, a recent co-crystal structure of the enzyme in complex with a substrate-derived peptide containing mechanism-based inhibitor explains the observed recognition motif sequence preferences in rhomboid substrates structurally, and provides a significant advance in the current understanding of rhomboid specificity and mechanism of rhomboid-family proteins.

[46] In some Gram-negative bacteria, including Shewanella and Vibrio, up to thirteen proteins are found with GlyGly-CTERM, a C-terminal homology domain consisting of a glycine-rich motif, a highly hydrophobic transmembrane helix, and a cluster of basic residues.

[citation needed] It is important to note, however, that there is no case yet established where a precise medical significance is fully validated.

Bioinformatic analysis highlights that some members of the rhomboid family lack the amino acid residues essential for proteolysis, implying that they cannot cleave substrates.

[59] This implies that the fundamental cellular quality control mechanism is exploited by multicellular organisms to regulate signalling between cells.

[59][60][61][62][63] Phylogenetic analysis indicates that rhomboids are in fact members of a larger rhomboid-like superfamily or clan, which includes the derlin proteins, also involved in ERAD.