8TUK

Alvinella ASCC1 KH and Phosphodiesterase/Ligase Domain

Summary for 8TUK

• Entry DOI: 10.2210/pdb8tuk/pdb
• Related: 8TLY
• Descriptor: Activating signal cointegrator 1 complex subunit 1, IMIDAZOLE, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: alkylation response, rna damage, kh domain, phosphoesterase domain, rna ligase domain, rna binding protein
• Biological source: Alvinella pompejana
• Total number of polymer chains: 1
• Total formula weight: 37067.85

Authors

Tsutakawa, S.E.,Tainer, J.A.,Arvai, A.S.,Chinnam, N.B. (deposition date: 2023-08-16, release date: 2024-07-10)

Primary citation

Chinnam, N.B.,Thapar, R.,Arvai, A.S.,Sarker, A.H.,Soll, J.M.,Paul, T.,Syed, A.,Rosenberg, D.J.,Hammel, M.,Bacolla, A.,Katsonis, P.,Asthana, A.,Tsai, M.S.,Ivanov, I.,Lichtarge, O.,Silverman, R.H.,Mosammaparast, N.,Tsutakawa, S.E.,Tainer, J.A.
ASCC1 structures and bioinformatics reveal a novel helix-clasp-helix RNA-binding motif linked to a two-histidine phosphodiesterase.
J.Biol.Chem., 300:107368-107368, 2024

PubMed Abstract: Activating signal co-integrator complex 1 (ASCC1) acts with ASCC-ALKBH3 complex in alkylation damage responses. ASCC1 uniquely combines two evolutionarily ancient domains: nucleotide-binding K-Homology (KH) (associated with regulating splicing, transcriptional, and translation) and two-histidine phosphodiesterase (PDE; associated with hydrolysis of cyclic nucleotide phosphate bonds). Germline mutations link loss of ASCC1 function to spinal muscular atrophy with congenital bone fractures 2 (SMABF2). Herein analysis of The Cancer Genome Atlas (TCGA) suggests ASCC1 RNA overexpression in certain tumors correlates with poor survival, Signatures 29 and 3 mutations, and genetic instability markers. We determined crystal structures of Alvinella pompejana (Ap) ASCC1 and Human (Hs) PDE domain revealing high-resolution details and features conserved over 500 million years of evolution. Extending our understanding of the KH domain Gly-X-X-Gly sequence motif, we define a novel structural Helix-Clasp-Helix (HCH) nucleotide binding motif and show ASCC1 sequence-specific binding to CGCG-containing RNA. The V-shaped PDE nucleotide binding channel has two His-Φ-Ser/Thr-Φ (HXT) motifs (Φ being hydrophobic) positioned to initiate cyclic phosphate bond hydrolysis. A conserved atypical active-site histidine torsion angle implies a novel PDE substrate. Flexible active site loop and arginine-rich domain linker appear regulatory. Small-angle X-ray scattering (SAXS) revealed aligned KH-PDE RNA binding sites with limited flexibility in solution. Quantitative evolutionary bioinformatic analyses of disease and cancer-associated mutations support implied functional roles for RNA binding, phosphodiesterase activity, and regulation. Collective results inform ASCC1's roles in transactivation and alkylation damage responses, its targeting by structure-based inhibitors, and how ASCC1 mutations may impact inherited disease and cancer.

PubMed: 38750793
DOI: 10.1016/j.jbc.2024.107368

Experimental method

X-RAY DIFFRACTION (1.15 Å)