The human laminin receptor precursor (LamR) has been identified as the receptor for the extracellular matrix molecule laminin, the pathogenic prion protein, and a variety of viruses. LamR and the p40 ribosomal protein are encoded by the same gene, demonstrating that human LamR is a protein that has acquired dual function through evolution, acting as both a cell-surface receptor and as a ribosomal protein. 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.

We solved the first high-resolution crystal structure of the majority of LamR (abbreviated LamR220) (PDB code 3BCH). LamR220 binds laminin with similar affinity as full-length LamR and inhibits Sindbis virus infection in vitro. Analyses of the solved crystal structures of human LamR and an ortholog, A. fulgidus S2p, reveal two regions of structural divergence. We have demonstrated that LamR220 specifically binds laminin in vitro, while A. fulgidus S2p does not exhibit laminin binding activity, which supports our hypothesis that differences between human LamR and A. fulgidus S2p are important for laminin binding.

Previously, characterization of LamR interactions with laminin has not been fully conclusive. Based on analyses of sequence conservation and of the crystal structures of human LamR and A. fulgidus S2p, we introduced point mutations into LamR220 to probe laminin binding. Mutation of Phe32 and Glu35 or Phe32 and Arg155 results in loss of laminin binding, which demonstrates that residues Phe32, Glu35, and Arg155 comprise a primary laminin binding site.

In the setting of cancer, interactions between LamR and laminin contribute to modifications of the extracellular matrix structure that affect tumor invasion and metastasis. The specific targeting of LamR with small-interfering RNA, blocking antibodies, and Sindbis viral vector has been associated with anti-tumor effects, demonstrating the importance of developing therapeutics that may interfere with LamR function. Structural determination of human LamR and characterization of a laminin binding domain will contribute to an understanding of how LamR interacts with laminin and may aid in the development of therapeutics that inhibit LamR function in the setting of cancer.