Structural and biochemical characterization of the cell fate determining nucleotidyltransferase fold protein MAB21L1.
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.
Ludwig-Maximilians-Universität München, Gene Center and Dept. of Biochemistry, Feodor-Lynen-Str. 25, 81377 Munich, Germany.
Carina C
CC
de Oliveira Mann
Proteros Biostructures GmbH, Bunsenstraße 7a, 82152 Martinsried, Germany.
Reiner
R
Kiefersauer
Ludwig-Maximilians-Universität München, Gene Center and Dept. of Biochemistry, Feodor-Lynen-Str. 25, 81377 Munich, Germany.
Gregor
G
Witte
Ludwig-Maximilians-Universität München, Gene Center and Dept. of Biochemistry, Feodor-Lynen-Str. 25, 81377 Munich, Germany.|Center for Integrated Protein Science (CIPSM), Ludwig-Maximilians Universität München, Feodor-Lynen Str. 25, 81377 Munich, Germany.
Karl-Peter
KP
Hopfner
D000595:Amino Acid Sequence; D001704:Biopolymers / Q000737:chemistry; D019070:Cell Lineage; D018360:Crystallography, X-Ray; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D001704:Biopolymers; D018398:Homeodomain Proteins; C499231:MAB21L1 protein, human