DPAM: A Domain Parser for AlphaFold Models

Zhang, Jing; Schaeffer, R. Dustin; Durham, Jesse; Cong, Qian; Grishin, Nick V.

doi:10.1101/2022.09.22.509116

Cited by 5 publications

(8 citation statements)

References 30 publications

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“…We developed a dedicated tool, Domain Parser for AlphaFold Models (DPAM), which is described in a separate paper ( 29 ). The DPAM recognizes globular domains from AF models based on a) interresidue distances, b) predicted aligned errors (PAE) between residues, and candidate homologous ECOD domains found by c) HHsuite and d) Dali ( 30 ).…”

Section: Resultsmentioning

confidence: 99%

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Classification of domains in predicted structures of the human proteome

Schaeffer

Zhang

Kinch

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Recent advances in protein structure prediction have generated accurate structures of previously uncharacterized human proteins. Identifying domains in these predicted structures and classifying them into an evolutionary hierarchy can reveal biological insights. Here, we describe the detection and classification of domains from the human proteome. Our classification indicates that only 62% of residues are located in globular domains. We further classify these globular domains and observe that the majority (65%) can be classified among known folds by sequence, with a smaller fraction (33%) requiring structural data to refine the domain boundaries and/or to support their homology. A relatively small number (966 domains) cannot be confidently assigned using our automatic pipelines, thus demanding manual inspection. We classify 47,576 domains, of which only 23% have been included in experimental structures. A portion (6.3%) of these classified globular domains lack sequence-based annotation in InterPro. A quarter (23%) have not been structurally modeled by homology, and they contain 2,540 known disease-causing single amino acid variations whose pathogenesis can now be inferred using AF models. A comparison of classified domains from a series of model organisms revealed expansions of several immune response-related domains in humans and a depletion of olfactory receptors. Finally, we use this classification to expand well-known protein families of biological significance. These classifications are presented on the ECOD website ( http://prodata.swmed.edu/ecod/index_human.php ).

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Section: Resultsmentioning

confidence: 99%

“…Domain classification data have been deposited in Zenodo ( 10.5281/zenodo.6998803 ) ( 66 ). The DPAM pipeline is open-source and its repository is maintained at GitHub ( https://github.com/CongLabCode/DPAM ) ( 67 ).…”

Section: Data Materials and Software Availabilitymentioning

confidence: 99%

Classification of domains in predicted structures of the human proteome

Schaeffer

Zhang

Kinch

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…The ability to detect distant homology is especially important for "hybrid" proteins such as C1, where global homology searches may be inconclusive (Figures 3A-C). Tools such as Foldseek 52 and the AlphaFold-based domain identification tool DPAM 53 are beginning to address these limitations and will empower future studies of structural homology, with continuing computational advances unlocking new biology. Pipelines like ours have great potential to reveal cryptic captured genes in classes of viruses beyond poxviruses, such as the emerging class of "giant viruses" that can encode thousands of genes, deepening our understanding of how viruses manipulate their hosts during infection.…”

Section: Discussionmentioning

confidence: 99%

Structural homology screens reveal poxvirus-encoded proteins impacting inflammasome-mediated defenses

Boys

Johnson

Quinlan

et al. 2023

Preprint

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Viruses acquire host genes via horizontal gene transfer and can express them to manipulate host biology during infections. Some viral and host homologs retain sequence identity, but evolutionary divergence can obscure host origins. We used structural modeling to compare vaccinia virus proteins with metazoan proteomes. We identified vaccinia A47L as a homolog of gasdermins, the executioners of pyroptosis. An X-ray crystal structure of A47 confirmed this homology and cell-based assays revealed that A47 inhibits pyroptosis. We also identified vaccinia C1L as the product of a cryptic gene fusion event coupling a Bcl-2 related fold with a pyrin domain. C1 associates with components of the inflammasome, a cytosolic innate immune sensor involved in pyroptosis, yet paradoxically enhances inflammasome activity, suggesting a benefit to poxvirus replication in some circumstances. Our findings demonstrate the potential of structural homology screens to reveal genes that viruses capture from hosts and repurpose to benefit viral fitness.

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“…Using a combination of sequence [ 51 ] and structural aligners [ 52 ], as well as consideration of residue-wise segment. The details of the DPAM algorithm are described elsewhere [ 53 ], here we briefly describe the overall method as well as changes made since the initial implementation. Using the predicted aligned errors (PAE) distributed with the predictions, regions that appear disordered or as linkers are excluded.…”

Section: Methodsmentioning

confidence: 99%

ECOD domain classification of 48 whole proteomes from AlphaFold Structure Database using DPAM2

Schaeffer,

Zhang,

Medvedev

et al. 2024

PLoS Comput Biol

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Protein structure prediction has now been deployed widely across several different large protein sets. Large-scale domain annotation of these predictions can aid in the development of biological insights. Using our Evolutionary Classification of Protein Domains (ECOD) from experimental structures as a basis for classification, we describe the detection and cataloging of domains from 48 whole proteomes deposited in the AlphaFold Database. On average, we can provide positive classification (either of domains or other identifiable non-domain regions) for 90% of residues in all proteomes. We classified 746,349 domains from 536,808 proteins comprised of over 226,424,000 amino acid residues. We examine the varying populations of homologous groups in both eukaryotes and bacteria. In addition to containing a higher fraction of disordered regions and unassigned domains, eukaryotes show a higher proportion of repeated proteins, both globular and small repeats. We enumerate those highly populated domains that are shared in both eukaryotes and bacteria, such as the Rossmann domains, TIM barrels, and P-loop domains. Additionally, we compare the sampling of homologous groups from this whole proteome set against our stable ECOD reference and discuss groups that have been enriched by structure predictions. Finally, we discuss the implication of these results for protein target selection for future classification strategies for very large protein sets.

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DPAM: A Domain Parser for AlphaFold Models

Cited by 5 publications

References 30 publications

Classification of domains in predicted structures of the human proteome

Classification of domains in predicted structures of the human proteome

Structural homology screens reveal poxvirus-encoded proteins impacting inflammasome-mediated defenses

ECOD domain classification of 48 whole proteomes from AlphaFold Structure Database using DPAM2

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