Abstract
The exceptionally conserved metazoan MAB21 proteins are implicated in cell fate decisions and share considerable sequence homology with the cyclic GMP-AMP synthase. cGAS is the major innate immune sensor for cytosolic DNA and produces the second messenger 2′-5′, 3′-5′ cyclic GMP-AMP. Little is known about the structure and biochemical function of other proteins of the cGAS-MAB21 subfamily, such as MAB21L1, MAB21L2 and MAB21L3. We have determined the crystal structure of human full-length MAB21L1. Our analysis reveals high structural conservation between MAB21L1 and cGAS but also uncovers important differences. Although monomeric in solution, MAB21L1 forms a highly symmetric double-pentameric oligomer in the crystal, raising the possibility that oligomerization could be a feature of MAB21L1. In the crystal, MAB21L1 is in an inactive conformation requiring a conformational change - similar to cGAS - to develop any nucleotidyltransferase activity. Co-crystallization with NTP identified a putative ligand binding site of MAB21 proteins that corresponds to the DNA binding site of cGAS. Finally, we offer a structure-based explanation for the effects of MAB21L2 mutations in patients with eye malformations. The underlying residues participate in fold-stabilizing interaction networks and mutations destabilize the protein. In summary, we provide a first structural framework for MAB21 proteins.
Highlights
Mutations of MAB21L2 result in drastic phenotypes and defects that lead to death in mid-gestation[17,18,19]
We provide a structure-based explanation for the effects of mutations in MAB21L2 associated with eye malformations and show that these mutations lead to destabilization of the fold
Single anomalous diffraction (SAD) data to 3.4 Å followed by phase improvement produced an interpretable electron density map that was used to build initial models for all ten copies in the asymmetric unit using non-crystallographic symmetry restrains
Summary
Mutations of MAB21L2 result in drastic phenotypes and defects that lead to death in mid-gestation[17,18,19]. Recent current whole exome sequencing projects identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with major eye malformations[24]. A homozygous mutation altering a different region of the protein Arg247Gln was associated with retinal coloboma. We provide the first crystal structure of a MAB21 protein and the structure of MAB21L1 bound to CTP. The human MAB21L1 structure exhibits a high degree of structural conservation with cGAS but features a number of differences. We provide a structure-based explanation for the effects of mutations in MAB21L2 associated with eye malformations and show that these mutations lead to destabilization of the fold
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