ECOD: An Evolutionary Classification of Protein Domains

Abstract

Understanding the evolution of a protein, including both close and distant relationships, often reveals insight into its structure and function. Fast and easy access to such up-to-date information facilitates research. We have developed a hierarchical evolutionary classification of all proteins with experimentally determined spatial structures, and presented it as an interactive and updatable online database. ECOD (Evolutionary Classification of protein Domains) is distinct from other structural classifications in that it groups domains primarily by evolutionary relationships (homology), rather than topology (or “fold”). This distinction highlights cases of homology between domains of differing topology to aid in understanding of protein structure evolution. ECOD uniquely emphasizes distantly related homologs that are difficult to detect, and thus catalogs the largest number of evolutionary links among structural domain classifications. Placing distant homologs together underscores the ancestral similarities of these proteins and draws attention to the most important regions of sequence and structure, as well as conserved functional sites. ECOD also recognizes closer sequence-based relationships between protein domains. Currently, approximately 100,000 protein structures are classified in ECOD into 9,000 sequence families clustered into close to 2,000 evolutionary groups. The classification is assisted by an automated pipeline that quickly and consistently classifies weekly releases of PDB structures and allows for continual updates. This synchronization with PDB uniquely distinguishes ECOD among all protein classifications. Finally, we present several case studies of homologous proteins not recorded in other classifications, illustrating the potential of how ECOD can be used to further biological and evolutionary studies.

Protein function annotation using protein domain family resources

“…CATH [35], SCOP [33] and ECOD [37]). PhyloFacts [20] also provides domain families in its resources which are sub-classified using SCI-PHY, as for the whole protein families.…”

Predictive and comparative analysis of Ebolavirus proteins

“…For proteins and domains without known structure, we considered putative structural templates detected by HHpred, 45 iTASSER 46,47 and known structures for proteins of similar function from other families of RNA virus in PDB and ECOD databases. 48 Once a candidate structural template was detected, we further validated its relationship to the Ebolavirus protein by similarity in function, compatibility between the predicted secondary structure 49 of the Ebolavirus protein and the 3D structure of the template, conservation of residues in the Ebolavirus protein that were aligned to the active sites of the template, and the consistency among multiple structural templates. Sequences of the structural templates and the ZEBOV protein were aligned by Promals3D 50,51 and the alignments were manually adjusted to ensure that the corresponding secondary structure elements in different templates were aligned together.…”

“…In addition, a scan of PDB sequences with the conserved pattern C-x (8)-C-x(4)-C-x(3)-H using ScanProsite 74 reveals exactly the same motif in CCCH zinc fingers (PDB id: 2d9n). All the CCCH zinc fingers belongs to one homologous group in the ECOD database, 48 and this family contains the N-terminal domain of the transcription antiterminator M2-1 from another Mononegavirales, Pneumovirus (4C3B 75 and 4CS7, 76 alignment shown in Fig. S1).…”

Evaluation system and web infrastructure for the second cryo-EM model challenge

“…Target-specific pages show evaluation results at three levels of target /model structural organization: quaternary structure ( Multimers tab), tertiary structure ( Monomers tab) and constituting domains (Cheng et al, 2014), if applicable ( Domains tab). For each of the structural organization levels, a user can browse the results by checking tabs corresponding to different assessment tracks.…”

“…Targets are split into domains by consulting the DomainParser (Guo et al, 2003), DDomain2 (Zhou et al, 2007) programs, and the ECOD (Cheng et al, 2014) database of structural domains. Organization of the web resource for the Domains evaluation is similar to that for the Monomers .…”