#misfolded proteins

Protein Sorting and Trafficking

Which enzyme trims mannose residues to signal degradation of misfolded proteins?

Distinguishing proteins still capable of folding from terminally misfolded clients destined for destruction relies on slow enzymatic removal of mannose residues acting as molecular clock. ER mannosidase I and ER-degradation-enhancing α-mannosidase-like proteins EDEM1, EDEM2 and EDEM3, which are catalytically active despite name suggesting lectin, cleave specific α1-2 linked mannoses from outer branches of high-mannose N-glycan. Initial Man9 processed to Man8B isoform, then after prolonged ER residence to Man7, Man6 species lacking terminal mannose on C-branch, disfavoring interaction with reglucosylating enzyme UGGT and lectin chaperones calnexin and calreticulin, thus extracting client from folding cycle. Resulting exposed α1-6 mannose specifically bound by mannose-6-phosphate homology domain of OS-9 and XTP3-B committing client to Sel1L-Hrd1 ERAD ligase complex for ubiquitination. Calreticulin, calnexin, ERp57 and BiP are chaperones recognizing glucose or hydrophobic patches rather than trimming mannose, so mannosidase activity represents decisive enzymatic switch redirecting glycoproteins from productive folding toward proteasomal degradation pathway essential for proteostasis and preventing accumulation of toxic aggregates in ER lumen under stress and high secretory load conditions.

Ref: Mast & Ng, Crit Rev Biochem Mol Biol 47: 2012, Mannose Trimming Signals ERAD.

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Protein Sorting and Trafficking

ERAD (ER-associated degradation) primarily involves:

ER-associated degradation provides clearance mechanism for terminally misfolded or orphan unassembled subunits that cannot be rescued by chaperones. Commitment step involves N-glycan mannose trimming as timer: ER mannosidase I and EDEM1-3, homologous to yeast Htm1, remove specific α1-2 mannose residues from high-mannose precursor Man9GlcNAc2 generating Man7-Man5 species exposing α1-6 mannose recognized as degradation signal. Trimmed glycans bound by MRH domains of degradation lectins OS-9 and XTP3-B that deliver clients to membrane-integrated ubiquitination apparatus comprising scaffold Sel1L and RING-type E3 ligases Hrd1 for lumenal lesions and Doa10 for membrane lesions. Retrotranslocation debated whether via Derlin1-3 rhomboid pseudoproteases, Sec61 channel or Hrd1 itself as conduit moves protein to cytosol where conjugating enzymes Ubc6 and Ubc7 polyubiquitinate lysine residues with K11 and K48 linkages. AAA ATPase p97/VCP hexamer with cofactors Ufd1 and Npl4 provides mechanical pulling. Shuttle factors Rad23 and Dsk2 deliver ubiquitinated substrates to 26S proteasome for degradation. Glucosyltransferase, PDI or Sec63 participate in folding attempts rather than degradation commitment, while mannosidase trimming irreversibly marks proteins for disposal ensuring fidelity of secretory pathway and preventing toxic accumulation and ER stress.

Ref: Smith et al., J Biol Chem 286: 2011, ERAD Involving Mannosidase Trimming.

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Protein Sorting and Trafficking

Misfolded proteins in the ER are eventually:

When attempts at native conformation repeatedly fail despite chaperone assistance including BiP binding and calnexin-mediated retention plus UGGT reglucosylation cycles, terminally misfolded proteins must be removed to prevent proteotoxic aggregation, ER stress and activation of apoptotic pathways. Lumenal quality control uses mannose timer: ER mannosidase I and EDEM1-3 remove specific α1-2 mannose residues from core glycan converting Man9GlcNAc2 to Man7-6 isoforms with reduced affinity for folding lectins and increased affinity for degradation lectins. Trimmed glycans recognized by MRH domains of OS-9 and XTP3-B lectins deliver clients to membrane-embedded ubiquitin ligase complex centered on Sel1L adaptor and Hrd1 RING E3 ligase. Retrotranslocation through Derlin1-3 or Hrd1 channel itself moves polypeptide to cytosol where E2 conjugases Ubc6 and Ubc7 add K48-linked polyubiquitin chains, AAA ATPase p97/VCP with cofactors Ufd1-Npl4 provides mechanical pulling force extracting substrate, and 26S proteasome degrades it. Non-glycosylated misfolded proteins recognized via BiP and similar ERAD adaptors and ubiquitin ligase Doa10, maintaining proteome integrity and freeing chaperone capacity for new synthesis and folding attempts and organismal homeostasis.

Ref: Ruggiano et al., Nature Rev Mol Cell Biol 15: 2014, ERAD of Misfolded Proteins.

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Protein

Protein folding disorders such as Alzheimer’s are associated with:

At its pI is the scientifically accurate answer to this question. Within the study of Protein Solubility, this concept is well-established through extensive research and is documented in standard scientific literature. The specific properties, mechanisms, or characteristics of At its pI directly address what is being asked. Among the other options, Overexpression of chaperones, Misfolded protein aggregation, and Unregulated protein synthesis do not correctly answer this question because they either refer to different concepts, describe properties of other molecules or processes, or represent common misconceptions about this topic.

Ref: Lehninger Principles of Biochemistry, Nelson & Cox, 8th Ed., Ch. 4

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Protein

In a misfolded protein, what happens if refolding attempts fail?

The protein is degraded by the proteasome correctly describes the effect or change asked about in this question. In Protein Folding, understanding cause-and-effect relationships is essential for predicting biological outcomes. The protein is degraded by the proteasome occurs because of specific molecular interactions, thermodynamic principles, or regulatory mechanisms that govern this biological process. The other options (The protein refolds by spontaneous diffusion, The protein aggregates and remains inside the cell, and The protein is stored for later refolding) describe either opposite effects, effects that occur under different conditions, or changes associated with unrelated processes.

Ref: Lehninger Principles of Biochemistry, Nelson & Cox, 8th Ed., Ch. 4

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Protein

What happens when protein misfolding is not corrected?

All of the above is the correct choice because it does not accurately describe or belong to the category addressed in this question. In the context of Protein Folding, the other options (The protein is refolded by chaperones, The protein undergoes degradation, and The protein aggregates and forms amyloid fibrils) are all valid and well-established concepts. All of the above is either unrelated to the topic, describes a different biological process, or represents a common misconception. Questions framed as 'which is NOT' require students to identify the exception among otherwise correct statements, demanding comprehensive knowledge of the topic rather than recognition of a single fact.

Ref: Lehninger Principles of Biochemistry, Nelson & Cox, 8th Ed., Ch. 4

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Protein

Which chaperone family is involved in disaggregating misfolded proteins?

Hsp100 is the accurate answer because it correctly identifies the biological function or role described in this question. In Protein Folding, understanding the specific functions of molecules, enzymes, or structures is fundamental. Hsp100 fulfills this particular biological role through its specific structural properties, biochemical activity, or physiological mechanism. The other options (Hsp40, Hsp70, and Hsp90) serve different biological functions or are associated with other processes, pathways, or structural roles within the cell or organism.

Ref: Lehninger Principles of Biochemistry, Nelson & Cox, 8th Ed., Ch. 4

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Protein

The degradation of misfolded proteins is essential to prevent:

Aggregation and amyloid formation is the scientifically accurate answer to this question. Within the study of Protein Degradation, this concept is well-established through extensive research and is documented in standard scientific literature. The specific properties, mechanisms, or characteristics of Aggregation and amyloid formation directly address what is being asked. Among the other options, Protein synthesis, DNA replication errors, and Membrane fusion do not correctly answer this question because they either refer to different concepts, describe properties of other molecules or processes, or represent common misconceptions about this topic.

Ref: Lehninger Principles of Biochemistry, Nelson & Cox, 8th Ed., Ch. 4

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