Integrin receptors regulate normal cell function processes such as signaling, cell migration, adhesion to the extracellular matrix, and leukocyte function. Talin recruitment to the membrane is necessary for its binding to and activation of integrin. Vertebrates have two highly conserved talin homologs that differ in their expression patterns. The F1-F3 FERM subdomains of cytoskeletal proteins resemble a cloverleaf but in talin1, its F1 and additional F0 align more linearly with its F2 and F3 subdomains. Here we present the talin2 crystal structure that has its F0-F1 di-subdomain displaying another unprecedented constellation, whereby F0-F1-F2 adopt a new cloverleaf-like arrangement. Mutating the corresponding residues in talin2 that abolish lipid binding in talin1 disrupt the binding of talin to the membrane, focal adhesion formation, and cell spreading. Our data provide the molecular details of the talin isoform specific functions.