Solution structure of the constant region of nuclear envelope protein LAP2reveals two LEM-domain structures: one binds BAF and the other binds DNA

The nuclear envelope proteins LAP2, emerin and MAN1 share a conserved simil ar to 40-residue 'LEM' motif. Loss of emerin causes Emery-Dreifuss muscular dystrophy. We have solved the solution NMR structure of the constant regio n of human LAP2 (residues 1-168). Human LAP2(1-168) has two structurally in dependent, non-interacting domains located at residues 1-50 ('LAP2-N') and residues 111-152 (LEM-domain), connected by an similar to 60-residue flexib le linker. The two domains are structurally homologous, comprising a helica l turn followed by two helices connected by an 11-12-residue loop. This mot if is shared by subdomains of T4 endonuclease VII and transcription factor rho, despite negligible (less than or equal to 15%) sequence identity. NMR chemical shift mapping demonstrated that the LEM-domain binds BAF (barrier- to-autointegration factor), whereas LAP2-N binds DNA. Both binding surfaces comprise helix 1, the N-terminus of helix 2 and the inter-helical loop. Bi nding selectivity is determined by the nature of the surface residues in th ese binding sites, which are predominantly positively charged for LAP2-N an d hydrophobic for the LEM-domain. Thus, LEM and LEM-like motifs form a comm on structure that evolution has customized for binding to BAF or DNA.