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Sci Rep. 2016 Jun 8;6:27498. doi: 10.1038/srep27498.

Structural and biochemical characterization of the cell fate determining nucleotidyltransferase fold protein MAB21L1.

Author information

1
Ludwig-Maximilians-Universität München, Gene Center and Dept. of Biochemistry, Feodor-Lynen-Str. 25, 81377 Munich, Germany.
2
Proteros Biostructures GmbH, Bunsenstraße 7a, 82152 Martinsried, Germany.
3
Center for Integrated Protein Science (CIPSM), Ludwig-Maximilians Universität München, Feodor-Lynen Str. 25, 81377 Munich, Germany.

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.

PMID:
27271801
PMCID:
PMC4897736
DOI:
10.1038/srep27498
[Indexed for MEDLINE]
Free PMC Article

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