The SOUL, or heme-binding protein HBP/SOUL, family represents a group of evolutionary conserved putative heme-binding proteins that contains a number of members in animal, plant and bacterial species. The structures of the murine form of HEBP1, or p22HBP, and the human form of HEBP2, or SOUL, have been determined in 2006 and 2011 respectively.

In this work we discuss the structures of HEBP1 and HEBP2 in light of new X-ray data for heme bound murine HEBP1. The interaction between tetrapyrroles and HEBP1, initially proven to be hydrophobic in nature, was thought to also involve electrostatic interactions between heme propionate groups and positively charged amino acid side chains. However, the new X-ray structure, and results from murine HEBP1 variants and human HEBP1, confirm the hydrophobic nature of the heme-HEBP1 interaction, resulting in K_d values in the low nanomolar range, and rules out any electrostatic stabilization. Results from NMR relaxation time measurements for human HEBP1 describe a rigid globular protein with no change in motional regime upon heme binding.

X-ray structures deposited in the PDB for human HEBP2 are very similar to each other and to the new heme-bound murine HEBP1 X-ray structure (backbone rmsd ca. 1 Å). Results from a HSQC spectrum centred on the histidine side chain Nδ-proton region for HEBP2 confirm that HEBP2 does not bind heme via H42 as no chemical shift differences were observed upon heme addition for backbone NH and Nδ protons.

A survey of the functions attributed to HEBP1 and HEBP2 over the last 20 years span a wide range of cellular pathways. Interestingly, many of them are specific to higher eukaryotes, particularly mammals and a potential link between heme release under oxidative stress and human HEBP1 is also examined using recent data. However, at the present moment, trying to relate function to the involvement of heme or tetrapyrrole binding, specifically, makes little sense with our current biological knowledge and can only be applied to HEBP1, as HEBP2 does not interact with heme.

We suggest that it may not be justified to call this very small family of proteins, heme-binding proteins. The family may be more correctly called “the SOUL family of proteins related to cellular fate” as, even though only HEBP1 binds heme tightly, both proteins may be involved in cell survival and/or proliferation.

SOUL 或血红素结合蛋白 HBP/SOUL 家族代表一组进化保守的假定血红素结合蛋白，其中包含动物、植物和 细菌物种中的许多成员。小鼠形式的 HEBP1 或 p22HBP 和人类形式的 HEBP2 或 SOUL 的结构已分别于 2006 年和 2011 年确定。

在这项工作中，我们根据血红素结合鼠 HEBP1 的新 X 射线数据讨论 HEBP1 和 HEBP2 的结构。四吡咯和 HEBP1 之间的相互作用最初被证明是疏水性的，被认为还涉及血红素丙酸酯基团和带正电荷的氨基酸侧链之间的静电相互作用。然而，新的 X 射线结构以及源自鼠 HEBP1 变体和人类 HEBP1 的结果证实了血红素-HEBP1 相互作用的疏水性，导致 K _d值在低纳摩尔范围内，并排除了任何静电稳定性。人 HEBP1 的 NMR 弛豫时间测量结果描述了一种刚性球状蛋白，在血红素结合后运动状态没有变化。

人 HEBP2 的 PDB 中沉积的 X 射线结构彼此非常相似，并且与新的血红素结合鼠 HEBP1 X 射线结构（骨架 rmsd 约 1 Å）非常相似。来自以 HEBP2 的组氨酸侧链 Nδ-质子区域为中心的 HSQC 光谱的结果证实 HEBP2 不通过 H42 结合血红素，因为在添加血红素时没有观察到主链 NH 和 Nδ 质子的化学位移差异。

对过去 20 年来 HEBP1 和 HEBP2 的功能的调查跨越了广泛的细胞途径。有趣的是，它们中的许多特定于高等真核生物，特别是哺乳动物，并且还使用最近的数据检查了氧化应激下血红素释放与人类 HEBP1 之间的潜在联系。然而，目前，试图将功能与血红素或四吡咯结合的参与联系起来，特别是，对我们目前的生物学知识没有多大意义，只能应用于 HEBP1，因为 HEBP2 不与血红素相互作用。

我们认为将这个非常小的蛋白质家族称为血红素结合蛋白可能是不合理的。该家族可能更准确地称为“与细胞命运相关的蛋白质的 SOUL 家族”，因为即使只有 HEBP1 与血红素紧密结合，这两种蛋白质也可能参与细胞存活和/或增殖。