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首页> 外文期刊>Journal of Molecular Biology >Structure-guided identification of a laminin binding site on the laminin receptor precursor.
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Structure-guided identification of a laminin binding site on the laminin receptor precursor.

机译：层粘连蛋白受体前体上层粘连蛋白结合位点的结构指导的鉴定。

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The 37/ 67-kDa human laminin receptor (LamR) is a cell surface receptor for laminin, prion protein, and a variety of viruses. Because of its wide range of ligands, LamR plays a role in numerous pathologies. LamR overexpression correlates with a highly invasive cell phenotype and increased metastatic ability, mediated by interactions between LamR and laminin. In addition, the specific targeting of LamR with small interfering RNAs, blocking antibodies, and Sindbis viral vectors confers anti-tumor effects. We adopted a structure-based approach to map a laminin binding site on human LamR by comparing the sequences and crystal structures of LamR and Archaeoglobus fulgidus S2p, a non-laminin-binding ortholog. Here, we identify a laminin binding site on LamR, comprising residues Phe32, Glu35, and Arg155, which are conserved among mammalian species. Mutation of these residues results in a significant loss of laminin binding. Further, recombinant wild-type LamR is able to act as a soluble decoy to inhibit cellular migration towards laminin. Mutation of this laminin binding site results in loss of migration inhibition, which demonstrates the physiological role of Phe32, Glu35, and Arg155 for laminin binding activity. Mapping of the LamR binding site should contribute to the development of therapeutics that inhibit LamR interactions with laminin and may aid in the prevention of tumor growth and metastasis.
机译：37/67 kDa人层粘连蛋白受体（LamR）是层粘连蛋白，病毒蛋白和多种病毒的细胞表面受体。由于其范围广泛的配体，LamR在许多病理学中都起着作用。 LamR过表达与LamR和层粘连蛋白之间的相互作用介导的高侵袭性细胞表型和增加的转移能力相关。另外，用小干扰RNA，阻断抗体和Sindbis病毒载体对LamR的特异性靶向赋予抗肿瘤作用。我们采用了一种基于结构的方法，通过比较LamR和fulgidus S2p（非层粘连蛋白直系同源物）的序列和晶体结构，在人LamR上定位层粘连蛋白结合位点。在这里，我们确定了LamR的层粘连蛋白结合位点，包括残基Phe32，Glu35和Arg155，它们在哺乳动物物种之间是保守的。这些残基的突变导致层粘连蛋白结合的显着丧失。此外，重组野生型LamR能够充当可溶性诱饵，以抑制细胞向层粘连蛋白的迁移。层粘连蛋白结合位点的突变导致失去迁移抑制，这证明了Phe32，Glu35和Arg155对层粘连蛋白结合活性的生理作用。 LamR结合位点的作图应有助于抑制LamR与层粘连蛋白相互作用的疗法的发展，并可能有助于预防肿瘤的生长和转移。

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