chaperone
Summary
Chaperone has two high-yield meanings. (1) Molecular chaperones (e.g., heat shock proteins such as Hsp60/Hsp70, and calnexin/calreticulin in the ER) assist protein folding, prevent aggregation, and target misfolded proteins for refolding or degradation. (2) A clinical chaperone is a trained third party present during sensitive physical exams (breast, genital, rectal) to protect patient and physician, and the patient may request or decline one.
Detail
MOLECULAR CHAPERONES (Biochemistry/Cell Biology) - Function: bind nascent or unfolded polypeptides to promote correct folding, prevent aggregation, and assist translocation across membranes and complex assembly. They do not become part of the final protein. - Heat shock proteins (HSPs): expression is induced by heat, hypoxia, and other stressors. - Hsp70 (with Hsp40/J-proteins) binds hydrophobic stretches of nascent chains in an ATP-dependent manner in the cytosol, mitochondria, and ER (BiP/GRP78). - Hsp60 (GroEL/GroES in bacteria; chaperonins) forms a barrel-shaped chamber that encloses misfolded proteins and refolds them using ATP. - Hsp90 stabilizes steroid hormone receptors and kinases (e.g., BCR-ABL, HER2). Hsp90 inhibitors are being studied in oncology. - Small HSPs such as αB-crystallin (lens) prevent aggregation. - ER quality control: calnexin and calreticulin bind monoglucosylated N-linked glycoproteins. BiP/GRP78 binds misfolded proteins. Proteins that fail to fold are retrotranslocated and ubiquitinated for proteasomal degradation (ERAD). Accumulation of misfolded proteins triggers the unfolded protein response (UPR). If the stress is prolonged, the cell undergoes apoptosis. - Clinical correlations: - Cystic fibrosis: the ΔF508 CFTR mutation causes misfolding. The protein is degraded in the ER and never reaches the membrane. Correctors (e.g., elexacaftor/tezacaftor/ivacaftor) act as pharmacologic chaperones that improve folding and trafficking. - α1-antitrypsin deficiency (Z allele): the misfolded protein polymerizes in hepatocytes. This causes liver cirrhosis and panacinar emphysema. - Neurodegenerative disease: misfolded proteins (amyloid-β, tau, α-synuclein, prions) overwhelm chaperone and proteasome capacity. - Osteogenesis imperfecta and other collagen disorders: defective procollagen folding. - Hsp47 is a collagen-specific chaperone in the ER. - Mycobacterium tuberculosis Hsp65 is an immunodominant antigen. Molecular mimicry between bacterial and human HSPs is proposed in autoimmunity (e.g., rheumatic fever, atherosclerosis).
CLINICAL CHAPERONE (Ethics/Professionalism, Step 2 CK) - Definition: an impartial third party, ideally a trained healthcare professional, who is present during sensitive exams or procedures (breast, pelvic, genital, rectal). Patient and physician are both protected. - Key points: - Offer a chaperone for every sensitive exam, regardless of the physician's or patient's gender. - The patient may request a chaperone at any time. If the patient declines, document it. If the physician feels a chaperone is needed, that is a reasonable request to make. - A family member or friend is not a substitute for a chaperone, but the patient may have one in addition. - Document the chaperone's name/role in the chart. - The chaperone should be able to see the exam and respect confidentiality. Maintain dignity (draping, explaining each step, obtaining consent). - Boards pearl: a patient requesting a chaperone should always be accommodated. If none is available, offer to reschedule rather than proceeding, unless the exam is emergent.
Distinguish the two uses by context: "chaperone" in a biochemistry or pathology stem refers to protein folding. In an ethics or physical-exam stem, it refers to a third-party observer.
Sources
- First Aid for the USMLE Step 1 (Biochemistry: protein folding and cellular trafficking; Heat shock proteins)
- Lippincott Illustrated Reviews: Biochemistry (protein folding, chaperones and misfolding diseases)
- Robbins & Cotran Pathologic Basis of Disease (cell injury, protein misfolding, ER stress)
- Harper's Illustrated Biochemistry
- AMA Code of Medical Ethics, Opinion 1.2.4: Use of Chaperones
- ACOG Committee Opinion No. 799: Sexual Misconduct / Use of Chaperones
- UWorld Step 1 and Step 2 CK Question Banks (Ethics and Biochemistry sections)
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