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In vitro reconstitution of Wnt acylation reveals structural determinants of substrate recognition by the acyltransferase human Porcupine
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Wnt proteins regulate a large number of processes including cellular growth, differentiation and tissue homeostasis through the highly conserved Wnt signaling pathway in metazoans. Porcupine (PORCN) is an endoplasmic reticulum (ER)-resident integral membrane enzyme that catalyzes posttranslational modification of Wnts with palmitoleic acid, an unsaturated lipid. This unique form of lipidation with palmitoleic acid is a vital step in the biogenesis and secretion of Wnt and PORCN inhibitors are currently in clinical trials for cancer treatment. However, PORCN-mediated Wnt lipidation has not been reconstituted in vitro with purified enzyme. Here, we report the first successful purification of human PORCN and confirm, through in vitro reconstitution with the purified enzyme, that PORCN is necessary and sufficient for Wntacylation. By systematically examining a series of substrate variants, we show that PORCN intimately recognizes the local structure of Wnt around the site of acylation. Our in vitro assay enabled us to examine the activity of PORCN with a range of fatty acyl-CoA’s with varying length and unsaturation. The selectivity of human PORCN across a spectrum of fatty acyl-CoA’s suggested that the kink in the unsaturated acyl chain is a key determinant PORCN-mediated catalysis. Finally, we show that two putative PORCN inhibitors that were discovered with cell-based assays indeed target human PORCN. Together, these results provide discrete, high-resolution biochemical insights into the mechanism of PORCN-mediated Wnt acylation and pave the way for further detailed biochemical and structural studies.

MBOAT family, protein lipidation, acyl selectivity, Acyl transferase, membrane enzyme, enzyme mechanism, Wnt pathway, post-translational modification (PTM), protein acylation, enzyme purification

논문정보 F1000선정
- 형식: Research article
- 게재일: 2018년 11월 (BRIC 등록일 2018-12-11)
- 연구진: 국외연구진
- 분야: Biochemistry
- 추천: Faculty of 1000 Biology
- 추천사유: Rapoport T and Sever N: F1000Prime Recommendation of [Lee CJ et al., J Biol Chem 2018]. In F1000Prime, 06 Dec 2018; 10.3410/f.734432261.793553171
발달장애, 지적장애 Armfield syndrome의 원인유전자 FAM50A 발견[Nat. Commun.]
발표: 김철희 (충남대학교)
일자: 2020년 8월 19일 (수) 오후 04시 (한국시간)
언어: 한국어
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다중오믹스 분석을 통한 식물 할로게나제 발견[Nat. Commun.]
발표: 김영훈 (Massachusetts Institute...)
일자: 2020년 8월 27일 (목) 오전 10시 (한국시간)
언어: 영어
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