Assembling multidomain protein structures through analogous global structural alignments

Abstract

Most proteins exist with multiple domains in cells for cooperative functionality. However, structural biology and protein folding methods are often optimized for single-domain structures, resulting in a rapidly growing gap between the improved capability for tertiary structure determination and high demand for multidomain structure models. We have developed a pipeline, termed DEMO, for constructing multidomain protein structures by docking-based domain assembly simulations, with interdomain orientations determined by the distance profiles from analogous templates as detected through domain-level structure alignments. The pipeline was tested on a comprehensive benchmark set of 356 proteins consisting of 2–7 continuous and discontinuous domains, for which DEMO generated models with correct global fold (TM-score > 0.5) for 86% of cases with continuous domains and for 100% of cases with discontinuous domain structures, starting from randomly oriented target-domain structures. DEMO was also applied to reassemble multidomain targets in the CASP12 and CASP13 experiments using domain structures excised from the top server predictions, where the full-length DEMO models showed a significantly improved quality over the original server models. Finally, sparse restraints of mass spectrometry-generated cross-linking data and cryo-EM density maps are incorporated into DEMO, resulting in improvements in the average TM-score by 6.3% and 12.5%, respectively. The results demonstrate an efficient approach to assembling multidomain structures, which can be easily used for automated, genome-scale multidomain protein structure assembly.

Comparative Transcriptomic and Proteomic Analyses Reveal a FluG‐Mediated Signaling Pathway Relating to Asexual Sporulation of Antrodia camphorata

“…The fluG , flbD , and ganB were reported to be involved in a FluG‐mediated conidiation signaling pathway . The transcriptional corepressor regulation of conidiation‐1 is required for normal circadian conidiation rhythm . The two homologous genes FaTUA1 and FaTUA2 encode the tubulin, which plays a central role in cell divisions, as the FaTUA1 deletion mutant of Fusarium asiaticum showed a significant decrease in conidiation, and produced abnormal conidia .…”

Modeled Structure of the Cell Envelope Proteinase of Lactococcus lactis

“…Comparison of protein structures and calculation of TM-scores and RMSD values was done using the TM-score and TM-align programs at University of Michigan 3 ( Zhang and Skolnick, 2004 ). Individual domains were assembled into larger models using the DEMO program ( Zhou et al, 2019 ).…”

Hypoxanthine-Guanine Phosphoribosyltransferase/adenylate Kinase From Zobellia galactanivorans: A Bifunctional Catalyst for the Synthesis of Nucleoside-5′-Mono-, Di- and Triphosphates

“…Thus, HGPRT from Leptospira interrogans (PDB id 4QRI) and AMPK structure from Geobacillus stearothermophilus (PDB id 1ZIN) were selected as templates. Then, a complete Zg HGPRT/AMPK 3D model was built through assembling the best homology models for both, HGPRT and AMPK domains, using replica-exchange Monte Carlo simulations integrated in Domain Enhanced Modeling server ( Zhou et al, 2019 ). A protein-protein docking using ClusPro ( Vajda et al, 2017 ) was performed to ensure the optimum quality of the dual domain homology model.…”