5ED3

crystal structure of human Hint1 complexing with AP5A

Summary for 5ED3

• Entry DOI: 10.2210/pdb5ed3/pdb
• Related: 5ECB 5ECZ 5ED5 5ED6 5EDE 5EFL 5EFP
• Descriptor: Histidine triad nucleotide-binding protein 1, ADENOSINE MONOPHOSPHATE, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: hydrolase, nucleotide binding, regulation of transcription, signal transduction
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 28633.86

Authors

Wang, J.,Fang, P.,Guo, M. (deposition date: 2015-10-20, release date: 2017-01-25, Last modification date: 2023-09-27)

Primary citation

Yu, J.,Liu, Z.,Liang, Y.,Luo, F.,Zhang, J.,Tian, C.,Motzik, A.,Zheng, M.,Kang, J.,Zhong, G.,Liu, C.,Fang, P.,Guo, M.,Razin, E.,Wang, J.
Second messenger Ap4A polymerizes target protein HINT1 to transduce signals in Fc epsilon RI-activated mast cells.
Nat Commun, 10:4664-4664, 2019

PubMed Abstract: Signal transduction systems enable organisms to monitor their external environments and accordingly adjust the cellular processes. In mast cells, the second messenger ApA binds to the histidine triad nucleotide-binding protein 1 (HINT1), disrupts its interaction with the microphthalmia-associated transcription factor (MITF), and eventually activates the transcription of genes downstream of MITF in response to immunostimulation. How the HINT1 protein recognizes and is regulated by ApA remain unclear. Here, using eight crystal structures, biochemical experiments, negative stain electron microscopy, and cellular experiments, we report that ApA specifically polymerizes HINT1 in solution and in activated rat basophilic leukemia cells. The polymerization interface overlaps with the area on HINT1 for MITF interaction, suggesting a possible competitive mechanism to release MITF for transcriptional activation. The mechanism depends precisely on the length of the phosphodiester linkage of ApA. These results highlight a direct polymerization signaling mechanism by the second messenger.

PubMed: 31604935
DOI: 10.1038/s41467-019-12710-8

Experimental method

X-RAY DIFFRACTION (1.309 Å)