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Proteolysis within the membrane: rhomboids revealed

Nature Reviews Molecular Cell Biology volume 5, pages 188–197 (2004)Cite this article

Key Points

  • Rhomboids are a newly discovered family of serine proteases that are conserved throughout evolution.

  • Unlike all other serine proteases, rhomboids do not cleave soluble substrates but instead cut protein transmembrane domains within the lipid bilayer. This is analogous to the intramembrane protein cleavage that is catalysed by presenilins, signal-peptide peptidase and site-2 protease, which are unrelated intramembrane proteases of other mechanistic classes.

  • Rhomboids were first characterized in Drosophila melanogaster, where Rhomboid-1 is the primary activator of intercellular signalling by the epidermal growth factor receptor. All rhomboids that have been studied so far release proteins in the extracellular or luminal direction; this distinguishes them from the other intramembrane proteases, almost all of which release cytoplasmic protein domains.

  • Although the biological roles of rhomboids in most organisms are not yet known, there is a subclass of mitochondrial rhomboids that, at least in yeast, controls mitochondrial membrane remodelling by cleaving a dynamin-like protein known as Mgm1. One bacterial rhomboid has been investigated and it regulates the emission of quorum-sensing signal.

  • As with the other intramembrane proteases, little is known about the catalytic mechanism of rhomboids. The highly conserved and catalytically essential residues are predicted to form a catalytic triad comparable to that in the classic soluble serine proteases, but how this operates in the context of catalysis in a lipid bilayer is uncertain. All intramembrane proteases have multiple transmembrane domains and it seems likely that these form a hydrophilic micro-environment around the catalytic centre.

  • Intramembrane proteolysis is rapidly emerging as a widespread and versatile signalling mechanism that is used to control a great variety of biological events.

Abstract

The rhomboids are a recently discovered family of serine proteases with the unusual property of cleaving proteins within their transmembrane domains. They are the most widely conserved polytopic membrane proteins discovered so far. Although not much is known about the spectrum of their biological roles, it is already clear that rhomboids control events as diverse as growth factor signalling and mitochondrial membrane dynamics. As with other intramembrane proteases, the molecular details of how proteolysis can occur in a lipid bilayer remain mysterious.

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Figure 1: Rhomboids are intramembrane serine proteases.
Figure 2: The basis of Spitz targeting.
Figure 3: A rhomboid controls bacterial intercellular signalling.
Figure 4: The role of yeast mitochondrial rhomboid.
Figure 5: Site-2-protease cleavage of SREBP in the Golgi apparatus.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Matthew Freeman

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Related links

Related links

DATABASES

Entrez

aarA

Flybase

Aph-1

Gurken

Notch

Pen-2

Rhomboid-1

Rhomboid-2

Rhomboid-3

Rhomboid-4

Rhomboid-7

SREBP

Spitz

Star

TACE

Saccharomyces genome database

Ccp1

Mgm1

Rbd1

Swiss-Prot

PARL

RHBDL1

RHBDL2

FURTHER INFORMATION

Matthew Freeman's laboratory

MEROPS, the peptidase database

Nature Horizon symposium on proteases

Glossary

METALLOPROTEASE

A protease that depends on a coordinated metal ion for its catalytic mechanism.

ASPARTYL PROTEASE

A protease that depends on two aspartate residues that are essential for catalysis.

SERINE PROTEASE

A protease that uses an activated serine as the nucleophile at the heart of its catalytic mechanism.

POLYTOPIC MEMBRANE PROTEIN

A protein with several transmembrane domains.

OXYANION

A catalytic intermediate of proteolysis by serine proteases; stabilization of this intermediate contributes to the overall proteolytic mechanism.

TYPE II PROTEINS

Transmembrane proteins with a cytoplasmic amino terminus.

AMPHIPATHIC

An α-helix in which the sequence of amino-acid residues produces distinct hydrophilic and hydrophobic faces.

EF HAND

A protein motif that potentially binds calcium.

CYTOCHROME-C PEROXIDASE

A yeast mitochondrial enzyme that removes potentially dangerous free radicals.

DYNAMIN

A large GTPase that controls endocytosis and probably other cellular events.

AAA PROTEASE

A family of ATP-dependent proteases that mediate degradation of membrane proteins; mitochondrial AAA proteases are either matrix localized (mAAA) or intermembrane-space localized (iAAA).

ADAM FAMILY

(ADAM, a disintegrin and metalloprotease). A family of extracellular metalloproteases named after their characteristic ADAM domain structure.

SREPB

(SREBP, sterol-response-element-binding protein). A membrane-tethered transcription factor that controls certain genes in the sterol biosynthetic pathway.

UNFOLDED PROTEIN RESPONSE

An endoplasmic reticulum (ER) stress response that adapts the secretory pathway to abnormal load and protects cells from the dangers of high levels of unfolded proteins.

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Freeman, M. Proteolysis within the membrane: rhomboids revealed. Nat Rev Mol Cell Biol 5, 188–197 (2004). https://doi.org/10.1038/nrm1334

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