Biology subjects

Al-Fatlawi, A.

Publications and source records attributed to Al-Fatlawi, A..

6 recordsLinked to original sources

bioRxiv2026

Structural alphabets approach performance of structural alignment in remote homology detection

MotivationRemote homology detection (RHD) is central to fold recognition and protein function annotation. While structural alignments provide a gold standard, they are computationally expensive. Encoding protein structures as sequences over structural alphabets offers a scalable alternative, but the relative performance of simple secondary-structure alphabets versus higher-resolution representations remains unclear. ResultsWe systematically compare 20-letter (3Di), 8-letter (Q8), and 3-letter (Q3) structural alphabets across three large-scale fold recognition benchmarks of increasing difficulty, using both advanced and basic sequence alignment algorithms. All three alphabets perform close to structural alignment gold standards and substantially outperform sequence-based methods. Remarkably, the minimal Q3 alphabet, distinguishing only helices, strands, and loops, achieves robust performance. We further demonstrate the practical utility of this finding in a protein function annotation task for a newly sequenced genome. Data AvailabilityBenchmark data are freely available at https://doi.org/10.6084/m9.figshare.c.8208161. Contactmichael.schroeder@tu-dresden.de Supplementary InformationSupplementary data are available online at the journal website.

bioinformatics↗

bioRxiv2025

Structural insights into FOXP2 multimerization and interactions from AlphaFold3 modeling

FOXP2 is a transcription factor critical for speech and language, yet its full-length structure remains unresolved experimentally. We used AlphaFold3 to model full-length human FOXP2 and its complexes. AlphaFold3 predicts that FOXP2 forms a symmetric homo-hexamer, in which oligomerization orders regions that are disordered in the monomer. This assembly may facilitate cooperative DNA binding via the forkhead DNA-binding domains (FHDs). The FHD shows variable sequence affinities; high-affinity sites yield broader interfaces and greater stabilization, consistent with SPR data. Mapping of disease variants and human-specific substitutions revealed clustering in regions predicted to be stabilized by hexamer assembly. Modeling the R553H mutation showed loss of DNA contact at a critical recognition helix, which may explain its impact on transcription. We modeled FOXP2 interactions with 12 partners using AlphaFold3-multimer, evaluating interface consistency across replicates. DNA-dependent interactions were predicted with FOXP1, FOXP4, Pin1, and CDK3, involving the LZ and zinc finger domains. Other predicted interactions were low-confidence and sensitive to FOXP2s dynamic behavior. This work generates a testable, in silico structure-function map of FOXP2 that provides a framework for future experimental validation.

bioinformatics↗

bioRxiv2024

Protein secondary structure and remote homology detection

1A protein can be represented by its primary, secondary, or tertiary structure. With recent advances in AI, there is now as much tertiary as primary structural data available. Fast and accurate search methods exist for both types of data, with searches over both representations being highly precise. However, primary structure data can sometimes be incomplete. As a result, tertiary structure has become the gold standard for remote homology detection. How does secondary structure perform in remote homology detection? Secondary structure interprets proteins as a sequence using an alphabet representing helices, strands, or loops. It shares its sequential nature with primary structure while retaining topological information similar to tertiary structure. To assess the effectiveness of secondary structure in remote homology detection, we devised a challenging classification task aimed at determining the superfamily membership of very distantly related protein domains. We used benchmarks from the CATH and SCOP databases and evaluated sequence and structure alignment algorithms on primary, secondary, and tertiary structures. As expected, both basic and advanced sequence alignment algorithms applied to primary structure achieved high precision, but their overall area under the curve was lower compared to the gold standard of structural alignment using tertiary structure. Surprisingly, a simple string comparison algorithm applied to secondary structure performed close to the gold standard. This result supports the hypothesis that key structural information is already encoded in secondary structure and suggests that secondary structure may be a promising representation to use when high-confidence structural data is unavailable, such as in cases involving protein flexibility and disorder.

bioinformatics↗

bioRxiv2024

The Rad52 superfamily as seen by AlphaFold

1Rad52, a highly conserved eukaryotic protein, plays a crucial role in DNA repair, especially in double-strand break repair. Recent findings reveal that its distinct structural features, including a characteristic {beta}-sheet and {beta}-hairpin motif, are shared with the lambda phage single-strand annealing proteins, Red{beta}, indicating a common superfamily. Our analysis of over 10,000 single-strand annealing proteins (SSAPs) across all kingdoms of life supports this hypothesis, confirming their possession of the characteristic motif despite variations in size and composition. We found that archaea, representing only 1% of the studied proteins, exhibit most of these variations. Through the examination of four representative archaeal SSAPs, we elucidate the structural relationship between eukaryotic and bacterial SSAPs, highlighting differences in {beta}-sheet size and {beta}-hairpin complexity. Furthermore, we identify an archaeal SSAP with a structure nearly identical to the human variant and screen over 100 million unannotated proteins for potential SSAP candidates. Our computational analysis complements existing sequence with structural evidence supporting the suggested orthology among five SSAP families across all kingdoms: Rad52, Red{beta}, RecT, Erf, and Sak3.

bioinformatics↗

bioRxiv2023

The BOD1L subunit of the mammalian SETD1A complex sustains the expression of DNA damage repair genes despite restraining H3K4 trimethylation

SETD1A is the histone 3 lysine 4 (H3K4) methyltransferase central to the mammalian version of the highly conserved eight subunit Set1 complex (Set1C) that apparently conveys H3K4 trimethylation (H3K4me3) onto all active Pol II promoters. Accordingly, the Setd1a mouse knock-out dies in early embryogenesis at the epiblast stage and mouse embryonic stem cells (ESCs) die when SETD1A is removed. We report that ESC death is accompanied by loss of expression of DNA repair genes and accumulating DNA damage. BOD1L and BOD1 are homologs of the yeast Set1C subunit, Shg1, and subunits of the mammalian SETD1A and B complexes. We show that the Shg1 homology region binds to a highly conserved central alpha-helix in SETD1A and B. Like mutagenesis of Shg1 in yeast, conditional mutagenesis of Bod1l in ESCs promoted increased H3K4 di- and tri-methylation but also, like loss of SETD1A, loss of expression of DNA repair genes, increased DNA damage and cell death. In contrast to similar losses of DNA repair gene expression, the converse changes in H3K4 methylation after loss of SETD1A or BOD1L implies that H3K4 methylation is not essential for expression of the target DNA repair genes. Because BOD1L becomes highly phosphorylated after DNA damage and acts to protect damaged replication forks, the SETD1A complex, and BOD1L in particular, are key nodes for the DNA damage repair network.

cell biology↗

bioRxiv2021

Mutations in bdcA and valS correlate with quinolone resistance in wastewater Escherichia Coli

Single mutations can confer resistance to antibiotics. Identifying such mutations can help to develop and improve drugs. Here, we systematically screen for candidate quinolone resistance-conferring mutations. We sequenced highly diverse wastewater E. coli and performed a genome-wide association study (GWAS) correlating over 200,000 mutations against quinolone resistance phenotypes. We uncovered 13 statistically significant mutations including one located at the active site of the biofilm dispersal genes bdcA and six silent mutations in the aminoacyl-tRNA synthetase valS. The study also recovered the known mutations in the topoisomerases gyrA and parC. In summary, we demonstrate that GWAS effectively and comprehensively identifies resistance mutations without a priori knowledge of targets and mode of action. The results suggest that bdcA and valS may be novel resistance genes with biofilm dispersal and translation as novel resistance mechanisms.

bioinformatics↗