The intravascular processing of triglyceride-rich lipoproteins depends on lipoprotein lipase (LPL) and GPIHBP1, a membrane protein of endothelial cells that binds LPL within the subendothelial spaces and shuttles it to the capillary lumen. In the absence of GPIHBP1, LPL remains mislocalized within the subendothelial spaces, causing severe hypertriglyceridemia (chylomicronemia). The N-terminal domain of GPIHBP1, an intrinsically disordered region (IDR) rich in acidic residues, is important for stabilizing LPL's catalytic domain against spontaneous and ANGPTL4-catalyzed unfolding. Here, we define several important properties of GPIHBP1's IDR. First, a conserved tyrosine in the middle of the IDR is posttranslationally modified by O-sulfation; this modification increases both the affinity of GPIHBP1-LPL interactions and the ability of GPIHBP1 to protect LPL against ANGPTL4-catalyzed unfolding. Second, the acidic IDR of GPIHBP1 increases the probability of a GPIHBP1-LPL encounter via electrostatic steering, increasing the association rate constant (kon) for LPL binding by >250-fold. Third, we show that LPL accumulates near capillary endothelial cells even in the absence of GPIHBP1. In wild-type mice, we expect that the accumulation of LPL in close proximity to capillaries would increase interactions with GPIHBP1. Fourth, we found that GPIHBP1's IDR is not a key factor in the pathogenicity of chylomicronemia in patients with the GPIHBP1 autoimmune syndrome. Finally, based on biophysical studies, we propose that the negatively charged IDR of GPIHBP1 traverses a vast space, facilitating capture of LPL by capillary endothelial cells and simultaneously contributing to GPIHBP1's ability to preserve LPL structure and activity.

中文翻译：

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GPIHBP1中带有硫酸化酪氨酸的无序酸性域可调节脂蛋白脂肪酶。

富含甘油三酸酯的脂蛋白的血管内加工取决于脂蛋白脂酶（LPL）和GPIHBP1，这是一种内皮细胞的膜蛋白，可将LPL结合在内皮下空间并将其穿梭到毛细血管腔中。在缺少GPIHBP1的情况下，LPL仍在内皮下间隙内定位不正确，从而导致严重的高甘油三酯血症（乳糜微粒血症）。GPIHBP1的N末端结构域是一个富含酸性残基的内在无序区（IDR），对于稳定LPL的催化结构域抵抗自发的和ANGPTL4催化的解折叠至关重要。在这里，我们定义了GPIHBP1的IDR的几个重要属性。首先，IDR中部的保守酪氨酸通过O-硫酸化进行翻译后修饰。这种修饰既增加了GPIHBP1-LPL相互作用的亲和力，又提高了GPIHBP1保护LPL免受ANGPTL4催化的折叠的能力。其次，GPIHBP1的酸性IDR通过静电操纵增加了GPIHBP1-LPL遇到的可能性，使LPL结合的缔合速率常数（kon）增加了> 250倍。第三，我们表明即使在没有GPIHBP1的情况下，LPL也会在毛细血管内皮细胞附近积聚。在野生型小鼠中，我们预计LPL在毛细管附近的积累会增加与GPIHBP1的相互作用。第四，我们发现GPIHBP1自身免疫综合症患者的乳糜微粒血症的致病性不是GPIHBP1的关键因素。最后，根据生物物理研究，我们建议GPIHBP1带负电的IDR穿越广阔的空间，