School of Molecular Sciences, Arizona State University, Tempe, AZ 85281, USA.
School of Life Sciences, Arizona State University, Tempe, AZ 85281, USA.
Structure. 2024 Aug 8;32(8):1184-1196.e4. doi: 10.1016/j.str.2024.04.013. Epub 2024 May 9.
The integrin Mac-1 (αβ, CD11b/CD18, CR3) is an adhesion receptor expressed on macrophages and neutrophils. Mac-1 is also a promiscuous integrin that binds a diverse set of ligands through its αI-domain. However, the binding mechanism of most ligands remains unclear. We have characterized the interaction of αI-domain with the cytokine pleiotrophin (PTN), a protein known to bind αI-domain and induce Mac-1-mediated cell adhesion and migration. Our data show that PTN's N-terminal domain binds a unique site near the N- and C-termini of the αI-domain using a metal-independent mechanism. However, a stronger interaction is achieved when an acidic amino acid in a zwitterionic motif in PTN's C-terminal domain chelates the divalent cation in the metal ion-dependent adhesion site of active αI-domain. These results indicate that αI-domain can bind ligands using multiple mechanisms and that the active αI-domain has a preference for motifs containing both positively and negatively charged amino acids.
整合素 Mac-1（αβ，CD11b/CD18，CR3）是一种表达于巨噬细胞和中性粒细胞上的黏附受体。Mac-1 也是一种混杂的整合素，通过其 αI 结构域结合多种配体。然而，大多数配体的结合机制仍不清楚。我们已经描述了αI 结构域与细胞因子多效蛋白（PTN）的相互作用，PTN 是一种已知结合αI 结构域并诱导 Mac-1 介导的细胞黏附和迁移的蛋白。我们的数据表明，PTN 的 N 端结构域通过非依赖金属的机制结合到αI 结构域的 N 端和 C 端附近的一个独特位点上。然而，当 PTN 的 C 端结构域中的一个两性离子模体中的酸性氨基酸螯合活性αI 结构域中金属离子依赖黏附位点的二价阳离子时，会产生更强的相互作用。这些结果表明，αI 结构域可以使用多种机制结合配体，并且活性αI 结构域优先与含有正电荷和负电荷氨基酸的模体结合。
