Structural Basis of Tumor Suppressor in Lung Cancer 1 (TSLC1) Binding to Differentially Expressed in Adenocarcinoma of the Lung (DAL-1/4.1B)

Abstract

Perturbed cell adhesion mechanisms are crucial for tumor invasion and metastasis. A cell adhesion protein, TSLC1 (tumor suppressor in lung cancer 1), is inactivated in a majority of metastatic cancers. DAL-1 (differentially expressed in adenocarcinoma of the lung protein), another tumor suppressor, binds through its FERM domain to the TSLC1 C-terminal, 4.1 glycophorin C-like, cytoplasmic domain. However, the molecular basis for this interaction is unknown. Here, we describe the crystal structure of a complex between the DAL-1 FERM domain and a portion of the TSLC1 cytoplasmic domain. DAL-1 binds to TSLC1 through conserved residues in a well defined hydrophobic pocket in the structural C-lobe of the DAL-1 FERM domain. From the crystal structure, it is apparent that Tyr 406 and Thr 408 in the TSLC1 cytoplasmic domain form the most important interactions with DAL-1, and this was also confirmed by surface plasmon resonance studies. Our results refute earlier exon deletion experiments that indicated that glycophorin C interacts with the ␣-lobe of 4.1 FERM domains.

Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1

“…Consistent with CADM1 having parallel function in ␤-cells, CADM1 coimmunoprecipitated DAL-1 (Fig. 6), a protein 4.1 family member also known as EPB41L3 and protein 4.1B and shown previously to interact with CADM1 in other cell types (10,44).…”

“…*P Ͻ 0.05; **P Ͻ 0.01; ***P Ͻ 0.005. CADM1, as has been demonstrated in a variety of cell types, plays an essential role in cytoskeletal organization and remodeling (10,11,39,44). It helps anchor F-actin to subplasmalemmal sites and binds proteins that regulate actin cytoskeletal dynamics (11,39).…”

【Original Contribution】 Characterization of Mouse Monoclonal Antibodies to Human Protein 4.1R FERM Domain: Epitope Mapping and Application to FERM Domain Binding to Red Blood Cell Inside-out Vesicles

“…The authors suggested in the same report that, by analogy with TSLC1 and ezrin, GPC may bind to the C-lobe of R30 12) . This result contradicts previous reports that show that GPC binds to the α-lobe of R30 8,9) .…”

“…X-ray crystal structural analysis of a complex between ezrin and a peptide of Tumor Suppressor Lung Cancer (TSLC)-1, a transmembrane protein whose amino acid sequence is highly similar to that of GPC, has revealed that the TSLC1 peptide binds to the C-lobe of ezrin 12) . The authors suggested in the same report that, by analogy with TSLC1 and ezrin, GPC may bind to the C-lobe of R30 12) .…”

A 130-kDa Protein 4.1B Regulates Cell Adhesion, Spreading, and Migration of Mouse Embryo Fibroblasts by Influencing Actin Cytoskeleton Organization

“…Transgenic mice lacking the full-length (ϳ130 kDa) isoform of 4.1B have impaired gait and motility associated with ultrastructural anomalies in myelinated axons (31,32). In both aspects of function, 4.1B interacts with cell adhesion molecules, notably CADM1/TSLC1 (8,36) in relation to tumor suppression and CASPR/paranodin/neurexin-4 (CNTP1) (37) in relation to the organization of paranodes and juxtparanodes of myelinated axons.…”