WBR0935

Author	PageAuthor::William J Gibson
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry
Sub Category	SubCategory::Hematology, SubCategory::General Principles
Prompt	[[Prompt::Lenolidamide is a highly effective chemotherapy against multiple myeloma. A scientist is investigating the anti-neoplatic mechanism of lenolidamide. She finds that addition of lenolidamide to multiple myeloma cells decreases the protein abundance of the plasma cell essential transcription factors IKZF1 and IKZF3. She finds that lenolidamide binds to the CRBN-CRL4 complex, which then induces a post-translational modification of IKZF1 and IKZF3. Which of the following enzymatic activities does CRBN-CRL4 most likely possess?]]
Answer A	AnswerA::Glycosyltransferase
Answer A Explanation	[[AnswerAExp::Incorrect: Glycosylation refers to the addition of a carbohydrate to a protein. The glycosylation of proteins does not target them for degradation. Glycosylation is often necessary for the proper function or folding of the modified protein. One example of a heavily glycosylated protein family is the heparin sulfate proteoglycans.]]
Answer B	AnswerB::Farnesyltransferase
Answer B Explanation	AnswerBExp::Incorrect: Farnesyl groups can be added to proteins for their proper localization to cell membranes. Farnesylation does not target proteins for degradation.
Answer C	AnswerC::Gamma-carboxylase
Answer C Explanation	AnswerCExp::Incorrect: Vitamin K is gamma-carboxylated for its normal function.
Answer D	AnswerD::Hydroxylase
Answer D Explanation	[[AnswerDExp::Incorrect: Hydroxylation refers to the addition of an –OH group to a compound. Hydroxylation is an important step in the synthesis of steroid compounds. Proline hydroxylation is accomplished with Vitamin C as a cofactor in the synthesis of collagen.]]
Answer E	AnswerE::Ubiquitin ligase
Answer E Explanation	AnswerEExp::Correct: Proteins can be targeted for degradation by the addition of ubiquitin molecules to lysine residues.
Right Answer	RightAnswer::E
Explanation	[[Explanation::In this question we are given that upon addition of lenolidamide, two transcription factors are post-translationally modified and then degraded. Thus, we need to find the post-translational modification that induces degradation of proteins: ubiquitination. Ubiquitination is a post translational modification (an addition to a protein after it has been made) where ubiquitin is attached to a substrate protein. The addition of ubiquitin to proteins signals for the degradation of the protein by the proteasome. Educational Objective: Proteins can be targeted for degradation by the addition of ubiquitin molecules to lysine residues. References: First Aid 2012 page 78 First Aid 2013 page 73 Lu G, Middleton RE, Sun H, et al. The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins. Science. 2013; Educational Objective: References: ]]
Approved	Approved::Yes
Keyword	WBRKeyword::Ubiquitin, WBRKeyword::Post-translational modification, WBRKeyword::Protein, WBRKeyword::Translation, WBRKeyword::Molecular biology, WBRKeyword::Cell
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