GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity.
GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity.
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DOI：
10.3389/fcell.2021.702508
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发表时间：
2021
影响因子：
5.5
通讯作者：
Ploug M
中科院分区：
文献类型：
--
作者：
Kristensen KK;Leth-Espensen KZ;Kumari A;Grønnemose AL;Lund-Winther AM;Young SG;Ploug M
富含甘油三酯的脂蛋白（TRL）的血管内处理对于输送膳食脂质以促进心脏和骨骼肌的能量代谢以及在白色脂肪组织中的储存至关重要。在过去的十年中，通过对脂蛋白脂肪酶（LPL）功能的新认识，阐明了沿着毛细血管管腔表面的 TRL 局部脂肪分解加工的机制。 LPL的专用转运蛋白，糖基磷脂酰肌醇锚定的高密度脂蛋白结合蛋白1（GPIHBP1）；及其内源性抑制剂血管生成素样 (ANGPTL) 蛋白 3、4 和 8。LPL 生物学的重要发现包括解析 LPL 的晶体结构，表明 LPL 作为单体而不是同型二聚体具有催化活性，并且 LPL 水解酶结构域的边界稳定性对于 LPL 活性的调节至关重要。另一个关键发现是了解 ANGPTL4 如何调节 LPL 活性。 ANGPTL4 与催化腔附近的 LPL 序列的结合触发了 LPL 水解酶结构域的协同和顺序展开，导致催化腔不可逆的崩溃和 LPL 活性的丧失。最近的研究强调了 ANGPTL3-ANGPTL8 复合物对于氧化器官（例如心脏、骨骼肌、棕色脂肪组织）中 LPL 活性的内分泌调节的重要性，但其分子机制尚未完全明确。关于 LPL-GPIHBP1 相互作用以及 GPIHBP1 如何将 LPL 移动到毛细血管腔中的作用位点也获得了新的见解。 GPIHBP1 是 LU (Ly6/uPAR) 结构域蛋白超家族的非典型成员，包含本质上无序且高度酸性的 N 末端延伸和富含二硫键的三指 LU 结构域。无序的酸性结构域和折叠的 LU 结构域对于 LPL 的稳定性和运输以及调节其对 ANGPTL4 介导的去折叠的敏感性至关重要。本综述重点关注血管内脂肪分解关键蛋白的生物学和生物化学的最新进展。
Intravascular processing of triglyceride-rich lipoproteins (TRLs) is crucial for delivery of dietary lipids fueling energy metabolism in heart and skeletal muscle and for storage in white adipose tissue. During the last decade, mechanisms underlying focal lipolytic processing of TRLs along the luminal surface of capillaries have been clarified by fresh insights into the functions of lipoprotein lipase (LPL); LPL’s dedicated transporter protein, glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1); and its endogenous inhibitors, angiopoietin-like (ANGPTL) proteins 3, 4, and 8. Key discoveries in LPL biology include solving the crystal structure of LPL, showing LPL is catalytically active as a monomer rather than as a homodimer, and that the borderline stability of LPL’s hydrolase domain is crucial for the regulation of LPL activity. Another key discovery was understanding how ANGPTL4 regulates LPL activity. The binding of ANGPTL4 to LPL sequences adjacent to the catalytic cavity triggers cooperative and sequential unfolding of LPL’s hydrolase domain resulting in irreversible collapse of the catalytic cavity and loss of LPL activity. Recent studies have highlighted the importance of the ANGPTL3–ANGPTL8 complex for endocrine regulation of LPL activity in oxidative organs (e.g., heart, skeletal muscle, brown adipose tissue), but the molecular mechanisms have not been fully defined. New insights have also been gained into LPL–GPIHBP1 interactions and how GPIHBP1 moves LPL to its site of action in the capillary lumen. GPIHBP1 is an atypical member of the LU (Ly6/uPAR) domain protein superfamily, containing an intrinsically disordered and highly acidic N-terminal extension and a disulfide bond–rich three-fingered LU domain. Both the disordered acidic domain and the folded LU domain are crucial for the stability and transport of LPL, and for modulating its susceptibility to ANGPTL4-mediated unfolding. This review focuses on recent advances in the biology and biochemistry of crucial proteins for intravascular lipolysis.
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影响因子：
20.1
作者：
Beigneux AP;Fong LG;Bensadoun A;Davies BS;Oberer M;Gårdsvoll H;Ploug M;Young SG
通讯作者：
Young SG
影响因子：
8.1
作者：
Chi X;Britt EC;Shows HW;Hjelmaas AJ;Shetty SK;Cushing EM;Li W;Dou A;Zhang R;Davies BSJ
通讯作者：
Davies BSJ
影响因子：
6.5
作者：
Chen, Yan Q.;Pottanat, Thomas G.;Konrad, Robert J.
通讯作者：
Konrad, Robert J.
影响因子：
4.8
作者：
Chi, Xun;Shetty, Shwetha K.;Davies, Brandon S. J.
通讯作者：
Davies, Brandon S. J.
DOI：
10.1073/pnas.1820171116
发表时间：
2019-05-21
影响因子：
11.1
作者：
Arora, Rishi;Nimonkar, Amitabh V.;Trauger, John W.
通讯作者：
Trauger, John W.