Protein quality control

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Parent
ER protein degradation
Response to protein misfolding
Degradation of misfolded or incomplete proteins
Gene Ontology
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The protein quality control ( engl. Protein quality control ) is in eukaryotic cells a cellular protective mechanism for the maintenance of a functional proteome and the survival of the cell is of fundamental importance. All secretory proteins synthesized in a cell are transported to the endoplasmic reticulum (ER) and subjected to quality control there. Wrongly folded proteins are broken down by the cytosolic ubiquitin-proteasome system . The correctly folded proteins are transported to their destinations, for example the lysosome , the Golgi apparatus , the cell membrane or the extracellular space .

description

The correct primary and tertiary structure of a protein is of crucial importance for the function of a protein . Only properly folded proteins can function properly and errors in protein folding lead to alternative structures that are not biologically active. The causes of incorrect protein folding can vary in nature. Gene mutations in exons that lead to changes in the amino acid sequence , i.e. the primary structure of the gene product , have a direct influence on the secondary and tertiary structure, or on the protein folding kinetics. Errors in transcription or translation can also lead to misfolding of the proteins. These are called defective proteins, defective ribosomal products ' ( Engl. Defective ribosomal products , drips). About 30% of all polypeptides and proteins produced by a mammalian cell are broken down by proteasomes with a half-life of less than ten minutes because they are incorrectly folded. The proportion of misfoldings varies considerably from protein to protein. In the case of sensitive and complex proteins, such as the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the proportion of incorrect folds can be 60 to 80%. In addition to the DRiPs caused by production errors, there are also proteins that have been damaged by toxic influences, such as ionizing radiation , which can cause protein oxidation , and are therefore no longer able to fulfill their function in the cell. For a cell, the detection and breakdown of misfolded and defective proteins is vital, as they would otherwise damage the cell permanently.

To ensure the quality of the proteins, a multi-stage system developed in the course of evolution , which runs in three phases. In the first phase, the so-called proofreading ( dt. , Proofreading ') is checked the protein. In the second phase an attempt is made to fold the protein with active support. If this attempt fails, the protein is broken down. If it succeeds, the protein is transported to its destination. These two possibilities are the third phase. In all three phases, chaperones ( chaperones ) play a central role. These proteins help identify faulty proteins. They serve as a platform for protein compartmentalization (the assignment of proteins to certain cell compartments ) and assembly (the assembly of individual protein components into structures of a higher order).

About three quarters of the misfolded proteins are broken down by the standard 26S proteasome, with the breakdown being regulated by the activity of the heat shock protein Hsc70 . Co-chaperones support Hsc70 in transporting the DRiPs to the proteasome. Ubiquitin is covalently bound as a molecular signal via the co-chaperone CHIP to the DRiPS via the C terminus . The signal is important in the proteasome to recognize that this protein is to be broken down. The activity of Hsc70 is regulated by the protein HSJ1 (also referred to as DNAJB2 - a homolog of HSP40). HSJ1 stimulates the hydrolysis of ATP on the Hsc70 so that it can bind stably to the polypeptide chain. The ubiquitinated polypeptide is also shielded by HSJ1 so that the ubiquitin is not split off before it reaches the proteasome.

The remaining quarter of misfolded proteins are broken down by the 20S proteasome without ubiquitination , independently of the 19S regulators and largely without the influence of the activity of Hsp70. Wrongly folded proteins make up the largest proportion of the proteins broken down by the proteasome and are the most important source of self-antigens of the main histocompatibility complex I (MHC I). An accumulation of misfolded proteins in the endoplasmic reticulum leads to the unfolded protein response .

The protein quality control takes place in the cell at three previously known locations.

  • In the cytoplasm (cytoplasmic protein quality control), Hsp70 chaperones bind to the polypeptides during protein biosynthesis or shortly afterwards and support the folding process while consuming ATP .
  • About 20% of all proteins are taken up via the secretory pathway through the cell membrane. These proteins come either from other cells that secrete these proteins or from exogenous sources, for example intravenously administered protein-based drugs (e.g. as part of enzyme replacement therapy ). For transport through the cell membrane, these proteins are completely unfolded and then have to be correctly folded again within the cells. Proteins that are incorrectly folded or not assembled are prevented from being transported further into their target compartment, for example the lysosome , pulled out of the endoplasmic reticulum and broken down proteasomally in the cytoplasm.
  • In the nucleus , although no proteins are synthesized, it is there yet a protein quality control of the ubiquitin ligase san1 instead. This enzyme causes the ubiquitination of proteins in the cell nucleus that have become abnormal as a result of damage in the course of their lifespan.

Medical aspects

The breakdown of defective proteins and the maintenance of a functioning proteome are of essential importance for every cell, and ultimately for the entire organism . Ensuring this is the task of protein quality control. Disturbances in the balance of protein quality control between protein folding and degradation lead to serious diseases that can be divided into three groups.

There are also diseases in which both the loss of function and the toxic protein deposition become pathological. An example of this is alpha-1 antitrypsin deficiency . A mutation in SERPINA1 gene which codes for the acute-phase protein α-1-antitrypsin - a protease inhibitor - encoded , causes misfolding of α-1-antitrypsin. α-1-antitrypsin is mainly expressed by hepatocytes in the liver . Because of the misfolding, it cannot be secreted by the hepatocytes and it forms intracellular deposits. The loss of function leads to progressive pulmonary emphysema in the affected patient , as the lack of α-1-antitrypsin means that the enzyme leukocyte elastase ( human leukocyte elastase , HLE) can destroy the lung structure unchecked. The deposits of α-1-antitrypsin in the hepatocytes lead to liver cirrhosis parallel to the pulmonary emphysema .

Pharmacological Aspects

A large number of genetic diseases that are based on a loss-of-function mutation are not caused by a reduced function of the protein, but rather by significantly reduced folding kinetics. In principle, these proteins are fully functional, but are separated and broken down by the protein quality control due to their incorrect folding. This is the case , for example, with many lysosomal storage diseases . One therapeutic approach is chaperone therapy . The administration of pharmacological chaperones should positively influence the protein folding kinetics of the lysosomal enzymes. The pharmacological chaperones are reversible inhibitors that serve as a template for the enzyme .

As a proteasome inhibitor, the drug bortezomib intervenes directly in protein quality control. By blocking the proteasome, vital proteolysis processes in the cells are suppressed. Both healthy and malignant cells ( cancer cells ) are affected. In contrast to cancer cells, normal cells can regenerate if treatment is interrupted at certain times. Bortezomib is approved in Europe for the treatment of multiple myeloma .

further reading

Individual evidence

  1. ↑ C. Taxis, p. 6.
  2. ↑ JW Yewdell, LC Antón, JR Bennink: Defective ribosomal products (DRiPs): a major source of antigenic peptides for MHC class I molecules? In: Journal of Immunology. Volume 157, Number 5, September 1996, pp. 1823-1826, PMID 8757297 . (Review).
  3. ↑ U. Schubert, LC Antón and a .: Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. In: Nature . Volume 404, Number 6779, April 2000, pp. 770-774, doi: 10.1038 / 35008096 . PMID 10783891 .
  4. ↑ SB Qian, JR Bennink, JW Yewdell: Quantitating defective ribosome products. In: Methods in molecular biology (Clifton, NJ). Volume 301, 2005, pp. 271-281, doi: 10.1385 / 1-59259-895-1: 271 . PMID 15917638 .
  5. ↑ RR Kopito: Biosynthesis and degradation of CFTR. In: Physiological reviews. Volume 79, Number 1, 1999, pp. S167-S173, PMID 9922380 . (Review).
  6. ^ A b c d e W. Hilt: The Ubiquitin Proteasome System in Protein Quality Control and Regulation. In: BIOspectrum. Volume 11, Number 4, 2005, pp. 446-449.
  7. ↑ C. Esser, S. Alberti, J. Höhfeld: Cooperation of molecular chaperones with the ubiquitin / proteasome system. In: Biochimica et biophysica acta . Volume 1695, Numbers 1-3, November 2004, pp. 171-188, doi: 10.1016 / j.bbamcr.2004.09.020 . PMID 15571814 . (Review).
  8. ↑ Sylvia Feil: Protein Quality Control . In: Chemistry in Our Time . tape 39 , no. 5 , October 2005, p. 308-308 , doi : 10.1002 / ciuz.200590065 .
  9. ↑ a b S. B. Qian, MF Princiotta and a .: Characterization of rapidly degraded polypeptides in mammalian cells reveals a novel layer of nascent protein quality control. In: The Journal of biological chemistry . Volume 281, Number 1, January 2006, pp. 392-400, doi: 10.1074 / jbc.M509126200 . PMID 16263705 .
  10. ↑ T. Sommer, C. Hirsch: San1p, checking up on nuclear proteins. In: Cell . Volume 120, Number 6, March 2005, pp. 734-736, doi: 10.1016 / j.cell.2005.03.003 . PMID 15797374 .
  11. ^ RG Gardner, ZW Nelson, DE Gottschling: Degradation-mediated protein quality control in the nucleus. In: Cell. Volume 120, Number 6, March 2005, pp. 803-815, doi: 10.1016 / j.cell.2005.01.016 . PMID 15797381 .
  12. ↑ a b c d e f D. N. Hebert, M. Molinari: In and out of the ER: protein folding, quality control, degradation, and related human diseases. In: Physiological reviews. Volume 87, number 4, October 2007, pp. 1377-1408, doi: 10.1152 / physrev.00050.2006 . PMID 17928587 . (Review).
  13. ^ S. Ishii, HH Chang et al. a .: Preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for Fabry disease. In: Journal of pharmacology and experimental therapeutics . Volume 328, Number 3, March 2009, pp. 723-731, doi: 10.1124 / jpet.108.149054 . PMID 19106170 .
  14. ↑ R. Hamanaka, T. Shinohara et al. a .: Rescue of mutant alpha-galactosidase A in the endoplasmic reticulum by 1-deoxygalactonojirimycin leads to trafficking to lysosomes. In: Biochimica et biophysica acta . Volume 1782, number 6, June 2008, pp. 408-413, doi: 10.1016 / j.bbadis.2008.03.001 . PMID 18381081 .
  15. ^ ÖAZ current: Bortezomib. ( Memento from September 30, 2007 in the Internet Archive )
  16. ↑ myelom.at: Velcade® - active ingredient bortezomib. ( Memento of January 15, 2012 in the Internet Archive ) Retrieved October 10, 2011.