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HTRA proteases: regulated proteolysis in protein quality control

Nature Reviews Molecular Cell Biology volume 12, pages 152–162 (2011)Cite this article

Subjects

Key Points

  • Several lines of evidence have implicated the high temperature requirement A (HTRA) family of homooligomeric Ser proteases in protein quality control.

  • HTRA proteases are implicated in bacterial virulence and stress response, photosynthesis in plants, and proliferation, migration and cell fate in mammals.

  • HTRA proteases share common principles of activation with classic Ser proteases such as trypsin, chymotrypsin and elastase. However, their unique architecture, including carboxy-terminal PDZ (postsynaptic density of 95 kDa, Discs large and zonula occludens 1) domains, is responsible for a remarkable structural and functional plasticity that allows cells to rapidly respond to the presence of misfolded or mislocalized polypeptides.

  • The activity of HTRA proteases is tightly regulated by their switching on and off by peptides that bind to the PDZ domains. Activation is usually reversible and can involve a change in oligomeric state.

  • The PDZ domains of HTRA proteases are involved in a great variety of functions, including allosteric activation, cooperativity, processivity, activation by oligomerization, cellular localization (including lipid binding) and sensing of protein-folding stress.

Abstract

Controlled proteolysis underlies a vast diversity of protective and regulatory processes that are of key importance to cell fate. The unique molecular architecture of the widely conserved high temperature requirement A (HTRA) proteases has evolved to mediate critical aspects of ATP-independent protein quality control. The simple combination of a classic Ser protease domain and a carboxy-terminal peptide-binding domain produces cellular factors of remarkable structural and functional plasticity that allow cells to rapidly respond to the presence of misfolded or mislocalized polypeptides.

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Figure 1: HtrA proteases regulate protein quality control pathways in the Escherichia coli cell envelope.
Figure 2: Biological functions of plant and mammalian HTRA proteases.
Figure 3: Architecture of HTRA proteases.
Figure 4: Principles of HTRA protease regulation.
Figure 5: Architecture of the HTRA PDZ domain.
Figure 6: Function of the PDZ domain in proteolysis.

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Acknowledgements

M.E. was supported by the Deutsche Forschungsgemeinschaft and T.C. by the Fonds zur Förderung der wissenschaftlichen Forschung, Austria, (I 235-B09) in the frame of the ERA-NET NEURON. The Research Institute of Molecular Pathology (IMP) is funded by Boehringer Ingelheim.

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  1. Research Institute of Molecular Pathology (IMP), Dr. Bohrgasse 7, Vienna, A-1030, Austria

    Tim Clausen

  2. Centre for Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Universitaetsstrasse, Essen, 45117, Germany

    Markus Kaiser, Robert Huber & Michael Ehrmann

  3. Max-Planck-Institute of Biochemistry, Am Klopferspitz 18A, Martinsried, 82152, Germany

    Robert Huber

  4. School of Biosciences, Cardiff University, Biomedical Building, Museum Avenue, Cardiff, CF10 3US, UK

    Robert Huber & Michael Ehrmann

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Glossary

Ser protease

An enzyme that hydrolyses peptide bonds using an active site Ser residue as a nucleophile.

Periplasm

A cellular compartment of Gram-negative bacteria that is located between the cytoplasmic and the outer membranes.

β-augmentation

The binding of a peptide ligand as an additional β-strand to an existing β-sheet.

Catalytic triad

In a catalytic triad, the reactivity of the catalytic Ser residue is modulated by two other polar side chains, typically a His and an Asp residue, that determine its nucleophilic character.

Oxyanion hole

During protein cleavage, an intermediate occurs that has a negatively charged carbonyl oxygen. This oxyanion is stabilized by two hydrogen bonds in the oxyanion hole of the protease, which is an amide nitrogen cradle formed by residues preceding the catalytic Ser residue.

Substrate-specificity pocket

The S1 substrate specificity pocket accommodates the side chain of the residue preceding the scissile bond of the substrate, and is one important determinant of specificity.

Allostery and cooperativity

The interaction of binding sites at a distance is termed allostery. It may lead to activation or inhibition by cooperativity between ligands when a ligand bound at one site affects the affinity of another site for its ligand by inducing transitions between distinct conformational states.

Disorder–order transition

Structural elements of proteins can be present in multiple statically and/or dynamically disordered conformations that, in the extreme case, cannot be traced by X-ray crystallography. Disorder of the ligand recognition site impedes enzymatic activity, and ligand binding or other, for example allosteric, signals induce a unique ordered conformation and activity.

Hill coefficient

The Hill coefficient quantifies the cooperativity of ligand binding by an allosteric protein and indicates the minimal number of interacting binding sites. A Hill coefficient of 1 indicates independent binding even when ligands are bound to different binding sites, and a coefficient of >1 reflects positive cooperativity.

Constitutive activity

Refers to an enzyme that is constantly active even in the absence of activating ligands. Constitutive activity can be a phenotype of mutations that affect regulation, causing conformational changes that abolish the need for activation.

CpG island

A genomic region that contains a high content of cytosine (C) and guanine (G) dinucleotides (the 'p' refers to the phosphodiester bond linking the two bases). CpG islands are found in many mammalian promoters, and unlike scattered CpGs throughout the genome, which are usually hypermethylated, promoter CpG islands are normally hypomethylated.

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Clausen, T., Kaiser, M., Huber, R. et al. HTRA proteases: regulated proteolysis in protein quality control. Nat Rev Mol Cell Biol 12, 152–162 (2011). https://doi.org/10.1038/nrm3065

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