Dataset Information

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

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.

SUBMITTER: de Oliveira Mann CC

PROVIDER: S-EPMC4897736 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

de Oliveira Mann Carina C CC Kiefersauer Reiner R Witte Gregor G Hopfner Karl-Peter KP

Scientific reports 20160608

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 ...[more]

PMID: 27271801

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Project description:Domains that belong to an immunoglobulin (Ig) fold are extremely abundant in cell surface receptors, which play significant roles in cell-cell adhesion and signaling. Although the structures of domains in an Ig fold share common topology of ?-barrels, functions of receptors in adhesion and signaling are regulated by the very heterogeneous binding between these domains. Additionally, only a small number of domains are directly involved in the binding between two multidomain receptors. It is challenging and time consuming to experimentally detect the binding partners of a given receptor and further determine which specific domains in this receptor are responsible for binding. Therefore, current knowledge in the binding mechanism of Ig-fold domains and their impacts on cell adhesion and signaling is very limited. A bioinformatics study can shed light on this topic from a systematic point of view. However, there is so far no computational analysis on the structural and functional characteristics of the entire Ig fold. We constructed nonredundant structural data sets for all domains in Ig fold, depending on their functions in cell adhesion and signaling. We found that data sets of domains in adhesion receptors show different binding preference from domains in signaling receptors. Using structural alignment, we further built a common structural template for each group of a domain data set. By mapping the protein-protein binding interface of each domain in a group onto the surface of its structural template, we found binding interfaces are highly overlapped within each specific group. These overlapped interfaces, we called consensus binding interfaces, are distinguishable among different data sets of domains. Finally, the residue compositions on the consensus interfaces were used as indicators for multiple machine learning algorithms to predict if they can form homotypic interactions with each other. The overall performance of the cross-validation tests shows that our prediction accuracies ranged between 0.6 and 0.8.

Dataset Information

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

Publications

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

Similar Datasets

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