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Spectroscopic and Mutagenesis Studies of Human PGRMC1

机译：人类PGRMC1的光谱和诱变研究

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Progesterone receptor membrane component 1 (PGRMC1) is a 25 kDa protein with an N-terminal transmembrane domain and a putative C-terminal cytochrome b5 domain. Heme-binding activity of PGRMC1 has been shown in various homologues of PGRMC1. Although the general definition of PGRMC1 is as a progesterone receptor, progesterone-binding activity has not been directly demonstrated in any of the purified PGRMC1 proteins fully loaded with heme. Here, we show that the human homologue of PGRMC1 (hPGRMC1) binds heme in a five-coordinate (5C) high-spin (HS) configuration, with an axial tyrosinate ligand, likely Y95. The negatively charged tyrosinate ligand leads to a relatively low redox potential of approximately -331 mV. The Y95C or Y95F mutation dramatically reduces the ability of the protein to bind heme, supporting the assignment of the axial heme ligand to Y95. On the other hand, the Y95H mutation retains similar to 90% of the heme-binding activity. The heme in Y95H is also 5CHS, but it has a hydroxide axial ligand, conceivably stabilized by the engineered-in H95 via an H-bond; CO binding to the distal ligand-binding site leads to an exchange of the axial ligand to a histidine, possibly H95. We show that progesterone binds to hPGRMC1 and introduces spectral changes that manifest conformational changes to the heme. Our data offer the first direct evidence supporting progesterone-binding activity of PGRMC1.
机译：孕酮受体膜成分1（PGRMC1）是一种25 kDa的蛋白质，具有N端跨膜结构域和推定的C端细胞色素b5结构域。 PGRMC1的血红素结合活性已经在PGRMC1的各种同源物中显示。尽管PGRMC1的一般定义是作为孕激素受体，但尚未在任何完全装有血红素的纯化PGRMC1蛋白中直接证明孕激素结合活性。在这里，我们显示PGRMC1（hPGRMC1）的人类同源物以五坐标（5C）高自旋（HS）配置结合血红素，并带有轴向酪氨酸盐配体，可能是Y95。带负电荷的酪氨酸盐配体导致约-331 mV的较低氧化还原电势。 Y95C或Y95F突变会大大降低蛋白质结合血红素的能力，从而支持将轴向血红素配体分配给Y95。另一方面，Y95H突变保留了约90％的血红素结合活性。 Y95H中的血红素也是5CHS，但它具有氢氧根轴向配体，可以想象是通过H-键通过H-键工程化而稳定化。 CO结合到远端配体结合位点导致轴向配体交换成组氨酸，可能是H95。我们表明，孕酮与hPGRMC1结合并引入光谱变化，该变化表明血红素的构象变化。我们的数据提供了支持PGRMC1孕酮结合活性的第一个直接证据。

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