#protein quality control

Protein Sorting and Trafficking

Which process ensures proper protein folding in the ER?

Achieving native conformation in ER lumen depends on integrated network of ATP-driven chaperones, lectin chaperones, oxidoreductases and peptidyl-prolyl isomerases operating in millimolar calcium, oxidizing environment with high protein concentration. BiP/HSPA5 abundant Hsp70 cycles through ATP-dependent binding to hydrophobic patches preventing aggregation and regulating UPR sensors IRE1, PERK, ATF6 via sequestration. Lectin chaperones calnexin type I membrane protein and calreticulin soluble paralog monitor monoglucosylated N-glycans generated by glucosidase trimming, retaining incompletely

Ref: Braakman & Hebert, Cold Spring Harb Perspect Biol 5: 2013, ER Folding Machinery.

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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

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 domain

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

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Protein Sorting and Trafficking

The removal of three glucose residues from N-linked glycosylated proteins ensures:

Initial processing of N-glycan precursor after transfer to polypeptide is choreographed to interface with lectin chaperone system. After en bloc transfer of Glc3Man9GlcNAc2, ER alpha-glucosidase I removes terminal α1-2 glucose producing diglucosylated species. ER glucosidase II, heterodimer of catalytic α subunit and mannose-6-phosphate receptor homology β subunit that retains enzyme in ER and senses glycan, removes second α1-3 glucose generating monoglucosylated Glc1Man9GlcNAc2 which is specific ligand for lectin chaperones calnexin and calreticulin. Binding to these lectins retains nascent g

Ref: Hammond et al., Nature 372: 1994, Glucose Trimming and Calnexin Binding.

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Protein

Molecular chaperones are often referred to as:

Heat shock proteins is the scientifically accurate answer to this question. Within the study of Protein Folding, this concept is well-established through extensive research and is documented in standard scientific literature. The specific properties, mechanisms, or characteristics of Heat shock proteins directly address what is being asked. Among the other options, Protein catalysts, Protein disulfide isomerases, and Folding repressors do not correctly answer this question because they either refer to different concepts, describe properties of other molecules or processes, or represent common

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 stateme

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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