chaperones

**1. Molecular chaperones (Biochemistry/Cell Biology)** - Function: Bind nascent or denatured polypeptides, stabilize them, and promote correct folding. They do not form part of the final protein structure. Many are induced by stress (heat shock proteins, HSPs), so they are also called "stress proteins." - Major families: - Hsp70 (e.g., DnaK in bacteria; BiP/GRP78 in the ER): bind exposed hydrophobic regions of nascent chains in an ATP-dependent manner, preventing premature misfolding and aggregation. - Hsp60 / chaperonins (GroEL/GroES in bacteria; TRiC in eukaryotes): barrel-shaped complexes that enclose misfolded proteins and use ATP hydrolysis to refold them. - Hsp90: stabilizes steroid hormone receptors and kinases (e.g., client proteins such as BCR-ABL, HER2). It is a cancer drug target. - Small HSPs, e.g., αB-crystallin in the lens. - ER chaperones: calnexin and calreticulin (lectin chaperones for glycoprotein folding), BiP, protein disulfide isomerase (PDI, forms disulfide bonds). - Others: prolyl cis-trans isomerase (cyclophilin, the target of cyclosporine). - Quality control: Misfolded proteins that can't be refolded are tagged with ubiquitin and degraded by the proteasome (ERAD in the ER). Persistent misfolding triggers the unfolded protein response (UPR) and, if unresolved, apoptosis. - Clinical correlations: - Cystic fibrosis: the ΔF508 CFTR mutation causes misfolding, ER retention, and proteasomal degradation. Correctors (lumacaftor, tezacaftor, elexacaftor) act as pharmacologic chaperones that help folding and trafficking to the membrane. - α1-antitrypsin deficiency: misfolded Z-protein accumulates in hepatocyte ER, causing liver cirrhosis (PAS-positive globules) and panacinar emphysema. - Prion diseases (PrPc to PrPsc): the misfolded β-sheet-rich form is protease-resistant and induces further misfolding. - Neurodegeneration: Alzheimer (β-amyloid, tau), Parkinson (α-synuclein), and Huntington disease involve protein misfolding and aggregation, with failure of chaperone and proteasome systems. - Other misfolding diseases: Gaucher and Fabry disease (chaperone therapy such as migalastat for amenable GLA mutations), and amyloidosis. - Heat shock response: HSPs are upregulated by fever, hypoxia, ischemia, and toxins, and protect cells from injury. - Collagen: HSP47 is the collagen-specific chaperone. Other collagen-folding defects are seen in osteogenesis imperfecta. - Bacterial/viral relevance: Chaperones are essential for protein folding in many pathogens. Hsp90 is a potential antifungal and antimicrobial target.

**2. Medical chaperone (Ethics/Professionalism, Step 2 CK/Step 3)** - A chaperone is an impartial third party (ideally a trained staff member, not a family member) who is present during sensitive examinations (breast, genital, rectal) or procedures. - Purpose: Provides emotional comfort and support, serves as a witness, protects the patient from abuse, protects the physician from false accusations, and helps ensure professional boundaries. - Key points: - Offer a chaperone regardless of the physician's or patient's gender. A patient has the right to request one, and the physician may request one as well. - If the patient declines, document the refusal. If the physician is uncomfortable proceeding without one, they may reschedule or offer alternatives. - Document the chaperone's presence and identity in the chart. - Use a professional interpreter if there's a language barrier. A chaperone is not the same as an interpreter. - Exam for minors: Chaperones or guardian presence are often appropriate, but respect adolescent confidentiality and consent rules. - Sexual contact with a patient is always unethical, even with a chaperone present, and is grounds for license revocation.

**Board pearl:** "Chaperone" on a biochemistry question means heat shock proteins (Hsp60/Hsp70/Hsp90), which help folding and prevent aggregation. On an ethics question it means a third-party witness for sensitive exams, which the physician should offer and document.