Degradation of Misfolded Secretory and Membrane Proteins and Associated Diseases

Ikjin Kim, University of Texas Health Science Center, San Antonio, Texas, USA
Hai Rao, University of Texas Health Science Center, San Antonio, Texas, USA

Published online: October 2010

DOI: 10.1002/9780470015902.a0022577

Proper folding and targeting of proteins are pivotal for the functioning of cells. Misfolded secretory and membrane proteins are selected for degradation by the proteasome, a multisubunit cytosolic protease. This disposal process termed endoplasmic reticulum-associated degradation (ERAD) includes recognition of misfolded proteins in the endoplasmic reticulum (ER), retrotranslocation of substrates from the ER to the cytosol, ubiquitylation of substrates by the ubiquitylation enzymes, targeting of substrates to the proteasome, preprocessing of the substrates for efficient proteasomal degradation and final cleavage of misfolded proteins by the proteasome. Malfunctioning of ERAD components or accumulation of misfolded substrates has been found to cause various human diseases ranging from neurodegenerative disorders to cancers. Understanding the mechanism underlying ERAD provides a critical stepping-stone to design drugs and develop preventative and therapeutic strategies against these diseases.

Key Concepts:

  • Misfolded secretory and membrane proteins are degraded by ERAD.
  • Malfunctioning of ERAD components or accumulation of misfolded substrates cause various human diseases.
  • ERAD is composed of multiple steps including substrates recognition, retrotranslocation, ubiquitylation, targeting of substrates to the proteasome and the cleavage of substrates by the proteasome.
  • ERAD substrates are recognised and sorted into different degradation pathways based on the location of the misfolded domain and the topology of the protein.
  • The retrotranslocation of the substrates from the ER to the cytosol is mediated by undefined channel proteins.
  • Retrotranslocated substrates are ubiquitylated by membrane associated E3 enzymes with the help from E1, E2 enzymes.
  • Postubiquitylation processes in ERAD include substrate extraction from the ER membrane, substrate delivery to the proteasome, preprocessing of the substrates and proteasomal degradation.

Keywords: ER; ERAD; proteolysis; ubiquitin; proteasome; protein folding; protein trafficking; secretory proteins; membrane proteins; ubiquitylation

Figure 1. Overview of ERAD pathway: (1) Misfolded proteins in ER are recognised by ER resident chaperones and retrotranslocated through ER translocon. (2) Cdc48 complex generate pulling force to take out the substrates from ER membrane, and subsequently membrane anchored E3 ligases build up ubiquitin chain on the substrates with the help of E1 and E2 enzymes. (3) Glycan chain on glycoprotein is cleaved off by Png1 for efficient proteasomal degradation, and (4) ubiquitin chain recognition adaptors such as UBL/UBA domain-containing proteins deliver the substrates to the proteasome. (5) Substrates docked onto the proteasome are deubiquitylated, unfolded and subsequently digested into small peptides by the proteasome.
Figure 2. The domain structure of key ERAD regulators. Abbreviations: NZF, NPL4 zinc finger; ring finger, really interesting new gene finger (E3 signature); RVP, retroviral protease domain; STI, heat shock chaperone-binding domain; TM; transmembrane domain; UBA, ubiquitin-associated domain; UBL, ubiquitin-like domain; UIM, ubiquitin-interacting motif; VWA, von Willebrand and XPCB, XPC-binding domain.
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Related Sub-Topics:

Basic Cell Biology, Protein, RNA and DNA | Membrane Proteins | Protein Folding, Evolution and Degradation | Posttranslational Modification | Protein Degradation
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Article Title: Degradation of Misfolded Secretory and Membrane Proteins and Associated Diseases
 
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Kim, Ikjin, and Rao, Hai(Oct 2010) Degradation of Misfolded Secretory and Membrane Proteins and Associated Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022577]