Ancient Origin of the New Developmental Superfamily DANGER

Nikolaidis, Nikolas; Chalkia, Dimitra; Watkins, D. Neil; Barrow, Roxanne K.; Snyder, Solomon H.; Rossum, Damian B. van; Patterson, Randen L.

doi:10.1371/journal.pone.0000204

Cited by 17 publications

(24 citation statements)

References 56 publications

(69 reference statements)

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“…The results plotted in Figure 2a reveal residues within the phosphotyrosine binding pocket and the hydrophobic pocket. These data are in excellent accord with the results of the study of Tokonzaba et al which demonstrate that both of these pockets are involved in phosphotyrosine-binding and lipid-binding by the SH2 domain of c-abl (Supplemental Figure 1a) (18). Further, many of the XLA-causing mutations themselves scored high in this analysis, in particular G302 and N365.…”

Section: Resultssupporting

confidence: 90%

“…These simulations also isolate amino acids which are integral to, and surround the known phosphotyrosine and hydrophobic binding pockets. These data correlate well with the NMR study of Tokonzaba et al (18), which demonstrated that these pockets were involved in binding phosphatidylinositol (4,5) bisphosphate (PIP(4,5) 2 ) by the SH2 domain contained in Abelson murine leukemia viral oncogene homolog 1 (c-abl), a distant relative of Tec kinases (18). Moreover, phylogenetic analysis of Tec kinase SH2 domains indicate that this region is evolving more rapidly than the other homologous domains contained in this family, suggesting this is a site of functional innovation.…”

Section: Introductionsupporting

confidence: 88%

“…We chose to base our study on SH2 domains as (i) there are numerous structures for these domains in the PDB library, (ii) they are a prominent class of well-studied adaptor domains (22), and (iii) a select few have been determined to bind lipids experimentally (18;23); although, none are annotated for this function computationally (e.g. SMART, Pfam, InterProScan, CDD, SVM).…”

Section: Resultsmentioning

confidence: 99%

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Phylogenetic Profiles Reveal Structural and Functional Determinants of Lipid-binding

Hong¹,

Chalkia²,

Ko³

et al. 2009

J Proteomics Bioinform

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One of the major challenges in the genomic era is annotating structure/function to the vast quantities of sequence information now available. Indeed, most of the protein sequence database lacks comprehensive annotation, even when experimental evidence exists. Further, within structurally resolved and functionally annotated protein domains, additional functionalities contained in these domains are not apparent. To add further complication, small changes in the amino-acid sequence can lead to profound changes in both structure and function, underscoring the need for rapid and reliable methods to analyze these types of data. Phylogenetic profiles provide a quantitative method that can relate the structural and functional properties of proteins, as well as their evolutionary relationships. Using all of the structurally resolved Src-Homology-2 (SH2) domains, we demonstrate that knowledge-bases can be used to create single-amino acid phylogenetic profiles which reliably annotate lipid-binding. Indeed, these measures isolate the known phosphotyrosine and hydrophobic pockets as integral to lipid-binding function. In addition, we determined that the SH2 domain of Tec family kinases bind to lipids with varying affinity and specificity. Simulating mutations in Bruton's tyrosine kinase (BTK) that cause X-Linked Agammaglobulinemia (XLA) predict that these mutations alter lipid-binding, which we confirm experimentally. In light of these results, we propose that XLA-causing mutations in the SH3-SH2 domain of BTK alter lipid-binding, which could play a causative role in the XLA-phenotype. Overall, our study suggests that the number of lipid-binding proteins is drastically underestimated and, with further development, phylogenetic profiles can provide a method for rapidly increasing the functional annotation of protein sequences.

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Section: Resultssupporting

confidence: 90%

Section: Introductionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

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Phylogenetic Profiles Reveal Structural and Functional Determinants of Lipid-binding

Hong¹,

Chalkia²,

Ko³

et al. 2009

J Proteomics Bioinform

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“…22). This consistent initiation site allows rps-BLAST to extend an alignment even between highly divergent sequences (22,(40)(41)(42)(43). This strategy is designed to amplify and encode the alignments possible for any given query sequence.…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic profiles reveal evolutionary relationships within the “twilight zone” of sequence similarity

Chang¹,

Hong²,

Ko³

et al. 2008

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

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Inferring evolutionary relationships among highly divergent protein sequences is a daunting task. In particular, when pairwise sequence alignments between protein sequences fall <25% identity, the phylogenetic relationships among sequences cannot be estimated with statistical certainty. Here, we show that phylogenetic profiles generated with the Gestalt Domain Detection Algorithm-Basic Local Alignment Tool (GDDA-BLAST) are capable of deriving, ab initio, phylogenetic relationships for highly divergent proteins in a quantifiable and robust manner. Notably, the results from our computational case study of the highly divergent family of retroelements accord with previous estimates of their evolutionary relationships. Taken together, these data demonstrate that GDDA-BLAST provides an independent and powerful measure of evolutionary relationships that does not rely on potentially subjective sequence alignment. We demonstrate that evolutionary relationships can be measured with phylogenetic profiles, and therefore propose that these measurements can provide key insights into relationships among distantly related and/or rapidly evolving proteins.ab initio ͉ retroelements ͉ reverse transcriptase ͉ GDDA-BLAST T he ''protein problem'' has remained unsolved despite decades of research (1, 2). In principle, one expects that the primary amino acid sequence of a protein determines its structure, function, and evolutionary (SF&E) characteristics. Yet, there still is no reliable method for predicting the native state structure of a protein and its function given only its sequence. In addition, inferring the evolutionary relationships among highly divergent protein and/or rapidly evolving sequences is a daunting task. In general, when pairwise sequence alignments between protein sequences fall below Ϸ25% identity (i.e., the ''twilight zone''), the assignment of positional homology is so difficult that it becomes impossible to safely estimate phylogenetic relationships (1, 3, 4). However, a small number of conserved residues (Ϸ8% identity) can coordinate the 3-D fold and/or function of proteins (5-7). Conversely, two proteins that share 88% identity can still retain independent structure and function (8).The aforementioned studies point out that quantitatively measuring data spaces in the protein world (i.e., the sequence, structure, and functional space that proteins occupy) is a fundamental question facing evolutionary/computational biologists, with further questions arising. Is there any equation that quantitatively connects these protein spaces to protein evolution? Which residues within amino acid sequences best reflect the evolutionary history of a given protein? Do proteins with similar sequence and structure necessarily share a common ancestor? Furthermore, if sequence and structure similarity suggest an evolutionary history, can weak similarities be strengthened by functional connections? All of these questions are essentially connected to the protein data space; however, to date they have not been clearly solved either ...

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“…Although cnidarians have been characterized as simple or primitive organisms based on their morphology, molecular studies of specific gene families have revealed an unexpected level of genomic, genetic, and transcriptional complexity in N. vectensis compared with Caenorhabditis elegans and Drosophila melanogaster (Miller et al 2005;Technau et al 2005;Nikolaidis et al 2007). Similarly, recent studies on M. brevicollis have revealed that choanoflagellates express a number of exclusively animal signaling and adhesion protein families (King et al 2003;Abedin and King 2008) and have lent support to the notion that choanoflagellates represent the closest known relatives of animals.…”

Section: Origin and Evolution Of The Animal Forminsmentioning

confidence: 99%

Origins and Evolution of the Formin Multigene Family That Is Involved in the Formation of Actin Filaments

Chalkia

Nikolaidis

Makałowski

et al. 2008

Molecular Biology and Evolution

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In eukaryotes, the assembly and elongation of unbranched actin filaments is controlled by formins, which are long, multidomain proteins. These proteins are important for dynamic cellular processes such as determination of cell shape, cell division, and cellular interaction. Yet, no comprehensive study has been done about the origins and evolution of this gene family. We therefore performed extensive phylogenetic and motif analyses of the formin genes by examining 597 prokaryotic and 53 eukaryotic genomes. Additionally, we used three-dimensional protein structure data in an effort to uncover distantly related sequences. Our results suggest that the formin homology 2 (FH2) domain, which promotes the formation of actin filaments, is a eukaryotic innovation and apparently originated only once in eukaryotic evolution. Despite the high degree of FH2 domain sequence divergence, the FH2 domains of most eukaryotic formins are predicted to assume the same fold and thus have similar functions. The formin genes have experienced multiple taxon-specific duplications and followed the birth-and-death model of evolution. Additionally, the formin genes experienced taxonspecific genomic rearrangements that led to the acquisition of unrelated protein domains. The evolutionary diversification of formin genes apparently increased the number of formin's interacting molecules and consequently contributed to the development of a complex and precise actin assembly mechanism. The diversity of formin types is probably related to the range of actin-based cellular processes that different cells or organisms require. Our results indicate the importance of gene duplication and domain acquisition in the evolution of the eukaryotic cell and offer insights into how a complex system, such as the cytoskeleton, evolved.

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Ancient Origin of the New Developmental Superfamily DANGER

Cited by 17 publications

References 56 publications

Phylogenetic Profiles Reveal Structural and Functional Determinants of Lipid-binding

Phylogenetic Profiles Reveal Structural and Functional Determinants of Lipid-binding

Phylogenetic profiles reveal evolutionary relationships within the “twilight zone” of sequence similarity

Origins and Evolution of the Formin Multigene Family That Is Involved in the Formation of Actin Filaments

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