Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095.
University of California, Los Angeles-United States Department of Energy Institute of Genomics and Proteomics, University of California, Los Angeles, CA 90095.
Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2211939120. doi: 10.1073/pnas.2211939120. Epub 2023 Jan 24.
(group A ) is a clinically important microbial pathogen that requires iron in order to proliferate. During infections, uses the surface displayed Shr receptor to capture human hemoglobin (Hb) and acquires its iron-laden heme molecules. Through a poorly understood mechanism, Shr engages Hb via two structurally unique N-terminal Hb-interacting domains (HID1 and HID2) which facilitate heme transfer to proximal NEAr Transporter (NEAT) domains. Based on the results of X-ray crystallography, small angle X-ray scattering, NMR spectroscopy, native mass spectrometry, and heme transfer experiments, we propose that Shr utilizes a "cap and release" mechanism to gather heme from Hb. In the mechanism, Shr uses the HID1 and HID2 modules to preferentially recognize only heme-loaded forms of Hb by contacting the edges of its protoporphyrin rings. Heme transfer is enabled by significant receptor dynamics within the Shr-Hb complex which function to transiently uncap HID1 from the heme bound to Hb's β subunit, enabling the gated release of its relatively weakly bound heme molecule and subsequent capture by Shr's NEAT domains. These dynamics may maximize the efficiency of heme scavenging by , enabling it to preferentially recognize and remove heme from only heme-loaded forms of Hb that contain iron.
（A 组）是一种临床重要的微生物病原体，它需要铁才能繁殖。在感染过程中，利用表面展示的 Shr 受体来捕获人类血红蛋白（Hb）并获取其含铁的血红素分子。通过一个尚未完全了解的机制，Shr 通过两个结构独特的 N 端血红蛋白相互作用域（HID1 和 HID2）与 Hb 结合，这有助于血红素向近端 NEAr 转运蛋白（NEAT）域转移。基于 X 射线晶体学、小角度 X 射线散射、NMR 光谱学、天然质谱和血红素转移实验的结果，我们提出 Shr 利用“盖帽和释放”机制从 Hb 中收集血红素。在该机制中，Shr 使用 HID1 和 HID2 模块通过接触其原卟啉环的边缘，优先识别仅带有血红素的 Hb 形式。血红素转移是通过 Shr-Hb 复合物内的受体动力学来实现的，该动力学可使 HID1 从与 Hb 的β亚基结合的血红素上短暂解帽，从而使相对较弱结合的血红素分子释放，并随后被 Shr 的 NEAT 域捕获。这些动力学可能最大限度地提高了 的血红素摄取效率，使其能够优先识别并从仅含有铁的血红素负载形式的 Hb 中去除血红素。
