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1.
Trop Lepid Res ; 31(1): 48-52, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34733399

RESUMO

Jonaspyge elizabethae n. sp. is described from southwestern Honduras. It is similar to the other two Jonaspyge O. Mielke, 2002 species in having metallic dark-blue wings with purple sheen, crenulate hindwing outer margin, and black body with orange palpi and an orange abdomen tip. It is diagnosed by bright-orange (instead of white) fringes and dark (instead of orange) cheeks. Genomic sequence analysis of Jonaspyge reveals that it is a close relative of Jonaspyge jonas (C. Felder & R. Felder, 1859) and Jonaspyge tzotzili (H. Freeman, 1969), differing from them by 5.3% in the COI DNA barcode. This new, third species of Jonaspyge is the most divergent member of the genus.

2.
Trop Lepid Res ; 31(1): 53-59, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34733400

RESUMO

Emesis eleanorae Gallardo & Grishin n. sp. is described from western Honduras. It differs from other species of Emesis Fabricius, 1807 in having a row of prominent iron-gray crescent-shaped postdiscal spots on both wings above, outlined by paler areas basad and mirrored as merlot-colored spots below, with the largest by the forewing costa, and in its females being bright golden-orange in color. Genomic sequence analysis of Emesis reveals that the new species belongs to the subgenus Aphacitis Hübner, [1819] and is sister to the clade containing Emesis diogenia Prittwitz, 1865 and Emesis heteroclita Stichel, 1929, and the clade of these three species is sister to Emesis vulpina Godman & Salvin, 1886.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34806023

RESUMO

Two new species of Hermeuptychia Forster, 1964 are described. Hermeuptychia sinuosa Grishin, sp. n. (type locality Guatemala: El Progreso, Morazán) is an isolated member of the genus that does not readily fit into known species groups, as suggested by its distinct male and female genitalia and COI DNA barcode sequences. It is distinguished from its congeners by prominently wavy submarginal lines, rounder wings and distinctive genitalia, and can typically be identified by a white dot, instead of an eyespot, near the ventral hindwing apex. Hermeuptychia occidentalis Grishin, sp. n. (type locality Mexico: Guerrero, Acapulco) belongs to the Hermeuptychia sosybius group as indicated by the presence of androconia on the dorsal surface of the wings, genitalia and COI DNA barcodes, and in addition to DNA characters, differs from its relatives in the shape of the uncus and female genitalia. Neotypes of Oreas strigata canthe Hübner, [1811] (type locality Suriname: Gelderland, Suriname River), Megisto acmenis Hübner, 1823 (type locality Argentina: Buenos Aires), and Satyrus cantheus Godart, [1824] (type locality USA: Florida, Pinellas Co., St. Petersburg) and lectotype of Euptychia celmis var. bonaërensis [sic] Burmeister, 1878 (type locality Argentina: Buenos Aires) are designated. These designations establish Hermeuptychia canthe as a valid species widely distributed in South America from Colombia to Bolivia and Southeast Brazil, Euptychia celmis var. bonaërensis [sic] Burmeister, 1878 as a junior objective synonym of Yphthimoides acmenis, and S. cantheus as a junior subjective synonym of Hermeuptychia sosybius (Fabricius, 1793). Papilio camerta Cramer, 1780 is treated as nomen dubium requiring further studies to determine an identity that is consistent with the original description, as it may be conspecific with Paryphthimoides poltys (Prittwitz, 1865) instead of being a Hermeuptychia species as currently assumed.

4.
Ecol Evol ; 11(17): 11615-11626, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34522328

RESUMO

Recently diverged butterfly populations in North America have been found to exhibit high levels of divergence on the Z chromosome relative to autosomes, as measured by fixation index, F st . The pattern of divergence appears to result from accumulation of incompatible alleles, obstructing introgression on the Z chromosome in hybrids (i.e., the large-Z effect); however, it is unknown whether this mechanism is sufficient to explain the data. Here, we simulate the effects of hybrid incompatibility on interbreeding butterfly populations using a model in which populations accumulate cross-incompatible alleles in allopatry prior to contact. We compute statistics for introgression and population divergence during contact between model populations and compare our results to those for 15 pairs of butterfly species interbreeding along a suture zone in central Texas. Time scales for allopatry and contact in the model are scaled to glacial and interglacial periods during which real populations evolved in isolation and contact. We find that the data for butterflies are explained well by an otherwise neutral model under slow fusion conditions. In particular, levels of divergence on the Z chromosome increase when interacting clusters of genes are closely linked, consistent with clusters of functionally related genes in butterfly genomes.

5.
Proteins ; 89(12): 1618-1632, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34350630

RESUMO

An evolutionary-based definition and classification of target evaluation units (EUs) is presented for the 14th round of the critical assessment of structure prediction (CASP14). CASP14 targets included 84 experimental models submitted by various structural groups (designated T1024-T1101). Targets were split into EUs based on the domain organization of available templates and performance of server groups. Several targets required splitting (19 out of 25 multidomain targets) due in part to observed conformation changes. All in all, 96 CASP14 EUs were defined and assigned to tertiary structure assessment categories (Topology-based FM or High Accuracy-based TBM-easy and TBM-hard) considering their evolutionary relationship to existing ECOD fold space: 24 family level, 50 distant homologs (H-group), 12 analogs (X-group), and 10 new folds. Principal component analysis and heatmap visualization of sequence and structure similarity to known templates as well as performance of servers highlighted trends in CASP14 target difficulty. The assigned evolutionary levels (i.e., H-groups) and assessment classes (i.e., FM) displayed overlapping clusters of EUs. Many viral targets diverged considerably from their template homologs and thus were more difficult for prediction than other homology-related targets. On the other hand, some targets did not have sequence-identifiable templates, but were predicted better than expected due to relatively simple arrangements of secondary structural elements. An apparent improvement in overall server performance in CASP14 further complicated traditional classification, which ultimately assigned EUs into high-accuracy modeling (27 TBM-easy and 31 TBM-hard), topology (23 FM), or both (15 FM/TBM).

6.
Elife ; 102021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34374645

RESUMO

TMEM120A, also named as TACAN, is a novel membrane protein highly conserved in vertebrates and was recently proposed to be a mechanosensitive channel involved in sensing mechanical pain. Here we present the single-particle cryogenic electron microscopy (cryo-EM) structure of human TMEM120A, which forms a tightly packed dimer with extensive interactions mediated by the N-terminal coiled coil domain (CCD), the C-terminal transmembrane domain (TMD), and the re-entrant loop between the two domains. The TMD of each TMEM120A subunit contains six transmembrane helices (TMs) and has no clear structural feature of a channel protein. Instead, the six TMs form an α-barrel with a deep pocket where a coenzyme A (CoA) molecule is bound. Intriguingly, some structural features of TMEM120A resemble those of elongase for very long-chain fatty acids (ELOVL) despite the low sequence homology between them, pointing to the possibility that TMEM120A may function as an enzyme for fatty acid metabolism, rather than a mechanosensitive channel.


Assuntos
Coenzima A/metabolismo , Elongases de Ácidos Graxos/química , Ácidos Graxos/química , Canais Iônicos/química , Canais Iônicos/metabolismo , Proteínas de Transporte , Fenômenos Eletrofisiológicos , Ácidos Graxos/classificação , Ácidos Graxos/metabolismo , Células HEK293 , Humanos , Canais Iônicos/genética , Metabolismo dos Lipídeos , Proteínas de Membrana , Membranas , Ligação Proteica
7.
Proteins ; 89(12): 1700-1710, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34455641

RESUMO

The high accuracy of some CASP14 models at the domain level prompted a more detailed evaluation of structure predictions on whole targets. For the first time in critical assessment of structure prediction (CASP), we evaluated accuracy of difficult domain assembly in models submitted for multidomain targets where the community predicted individual evaluation units (EUs) with greater accuracy than full-length targets. Ten proteins with domain interactions that did not show evidence of conformational change and were not involved in significant oligomeric contacts were chosen as targets for the domain interaction assessment. Groups were ranked using complementary interaction scores (F1, QS score, and Jaccard coefficient), and their predictions were evaluated for their ability to correctly model inter-domain interfaces and overall protein folds. Target performance was broadly grouped into two clusters. The first consisted primarily of targets containing two EUs wherein predictors more broadly predicted domain positioning and interfacial contacts correctly. The other consisted of complex two-EU and three-EU targets where few predictors performed well. The highest ranked predictor, AlphaFold2, produced high-accuracy models on eight out of 10 targets. Their interdomain scores on three of these targets were significantly higher than all other groups and were responsible for their overall outperformance in the category. We further highlight the performance of AlphaFold2 and the next best group, BAKER-experimental on several interesting targets.

8.
Proteins ; 89(12): 1673-1686, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34240477

RESUMO

This report describes the tertiary structure prediction assessment of difficult modeling targets in the 14th round of the Critical Assessment of Structure Prediction (CASP14). We implemented an official ranking scheme that used the same scores as the previous CASP topology-based assessment, but combined these scores with one that emphasized physically realistic models. The top performing AlphaFold2 group outperformed the rest of the prediction community on all but two of the difficult targets considered in this assessment. They provided high quality models for most of the targets (86% over GDT_TS 70), including larger targets above 150 residues, and they correctly predicted the topology of almost all the rest. AlphaFold2 performance was followed by two manual Baker methods, a Feig method that refined Zhang-server models, two notable automated Zhang server methods (QUARK and Zhang-server), and a Zhang manual group. Despite the remarkable progress in protein structure prediction of difficult targets, both the prediction community and AlphaFold2, to a lesser extent, faced challenges with flexible regions and obligate oligomeric assemblies. The official ranking of top-performing methods was supported by performance generated PCA and heatmap clusters that gave insight into target difficulties and the most successful state-of-the-art structure prediction methodologies.

9.
Science ; 373(6557): 871-876, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34282049

RESUMO

DeepMind presented notably accurate predictions at the recent 14th Critical Assessment of Structure Prediction (CASP14) conference. We explored network architectures that incorporate related ideas and obtained the best performance with a three-track network in which information at the one-dimensional (1D) sequence level, the 2D distance map level, and the 3D coordinate level is successively transformed and integrated. The three-track network produces structure predictions with accuracies approaching those of DeepMind in CASP14, enables the rapid solution of challenging x-ray crystallography and cryo-electron microscopy structure modeling problems, and provides insights into the functions of proteins of currently unknown structure. The network also enables rapid generation of accurate protein-protein complex models from sequence information alone, short-circuiting traditional approaches that require modeling of individual subunits followed by docking. We make the method available to the scientific community to speed biological research.


Assuntos
Aprendizado Profundo , Conformação Proteica , Dobramento de Proteína , Proteínas/química , Proteínas ADAM/química , Sequência de Aminoácidos , Simulação por Computador , Microscopia Crioeletrônica , Cristalografia por Raios X , Bases de Dados de Proteínas , Proteínas de Membrana/química , Modelos Moleculares , Complexos Multiproteicos/química , Redes Neurais de Computação , Subunidades Proteicas/química , Proteínas/fisiologia , Receptores Acoplados a Proteínas G/química , Esfingosina N-Aciltransferase/química
10.
ACS Omega ; 6(24): 15698-15707, 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34179613

RESUMO

Domain classifications are a useful resource for computational analysis of the protein structure, but elements of their composition are often opaque to potential users. We perform a comparative analysis of our classification ECOD against the SCOPe, SCOP2, and CATH domain classifications with respect to their constituent domain boundaries and hierarchal organization. The coverage of these domain classifications with respect to ECOD and to the PDB was assessed by structure and by sequence. We also conducted domain pair analysis to determine broad differences in hierarchy between domains shared by ECOD and other classifications. Finally, we present domains from the major facilitator superfamily (MFS) of transporter proteins and provide evidence that supports their split into domains and for multiple conformations within these families. We find that the ECOD and CATH provide the most extensive structural coverage of the PDB. ECOD and SCOPe have the most consistent domain boundary conditions, whereas CATH and SCOP2 both differ significantly.

11.
Sci Rep ; 11(1): 7996, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846496

RESUMO

Bumble bees exhibit exceptional diversity in their segmental body coloration largely as a result of mimicry. In this study we sought to discover genes involved in this variation through studying a lab-generated mutant in bumble bee Bombus terrestris, in which the typical black coloration of the pleuron, scutellum, and first metasomal tergite is replaced by yellow, a color variant also found in sister lineages to B. terrestris. Utilizing a combination of RAD-Seq and whole-genome re-sequencing, we localized the color-generating variant to a single SNP in the protein-coding sequence of transcription factor cut. This mutation generates an amino acid change that modifies the conformation of a coiled-coil structure outside DNA-binding domains. We found that all sequenced Hymenoptera, including sister lineages, possess the non-mutant allele, indicating different mechanisms are involved in the same color transition in nature. Cut is important for multiple facets of development, yet this mutation generated no noticeable external phenotypic effects outside of setal characteristics. Reproductive capacity was reduced, however, as queens were less likely to mate and produce female offspring, exhibiting behavior similar to that of workers. Our research implicates a novel developmental player in pigmentation, and potentially caste, thus contributing to a better understanding of the evolution of diversity in both of these processes.


Assuntos
Abelhas/genética , Genoma de Inseto , Sequenciamento de Nucleotídeos em Larga Escala , Mutação/genética , Pigmentação/genética , Sequenciamento Completo do Genoma , Sequência de Aminoácidos , Animais , Sequência Conservada/genética , Genes de Insetos , Estudo de Associação Genômica Ampla , Proteínas de Insetos/química , Proteínas de Insetos/genética , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Domínios Proteicos
12.
J Inherit Metab Dis ; 44(4): 949-960, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33855712

RESUMO

Glutamyl-tRNA synthetase 2 (encoded by EARS2) is a mitochondrial aminoacyl-tRNA synthetase required to translate the 13 subunits of the electron transport chain encoded by the mitochondrial DNA. Pathogenic EARS2 variants cause combined oxidative phosphorylation deficiency, subtype 12 (COXPD12), an autosomal recessive disorder involving lactic acidosis, intellectual disability, and other features of mitochondrial compromise. Patients with EARS2 deficiency present with variable phenotypes ranging from neonatal lethality to a mitigated disease with clinical improvement in early childhood. Here, we report a neonate homozygous for a rare pathogenic variant in EARS2 (c.949G>T; p.G317C). Metabolomics in primary fibroblasts from this patient revealed expected abnormalities in TCA cycle metabolites, as well as numerous changes in purine, pyrimidine, and fatty acid metabolism. To examine genotype-phenotype correlations in COXPD12, we compared the metabolic impact of reconstituting these fibroblasts with wild-type EARS2 versus four additional EARS2 variants from COXPD12 patients with varying clinical severity. Metabolomics identified a group of signature metabolites, mostly from the TCA cycle and amino acid metabolism, that discriminate between EARS2 variants causing relatively mild and severe COXPD12. Taken together, these findings indicate that metabolomics in patient-derived fibroblasts may help establish genotype-phenotype correlations in EARS2 deficiency and likely other mitochondrial disorders.

13.
J Mol Biol ; 433(11): 166915, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33676930

RESUMO

Deleterious single amino acid variation (SAV) is one of the leading causes of human diseases. Evaluating the functional impact of SAVs is crucial for diagnosis of genetic disorders. We previously developed a deep convolutional neural network predictor, DeepSAV, to evaluate the deleterious effects of SAVs on protein function based on various sequence, structural, and functional properties. DeepSAV scores of rare SAVs observed in the human population are aggregated into a gene-level score called GTS (Gene Tolerance of rare SAVs) that reflects a gene's tolerance to deleterious missense mutations and serves as a useful tool to study gene-disease associations. In this study, we aim to enhance the performance of DeepSAV by using expanded datasets of pathogenic and benign variants, more features, and neural network optimization. We found that multiple sequence alignments built from vertebrate-level orthologs yield better prediction results compared to those built from mammalian-level orthologs. For multiple sequence alignments built from BLAST searches, optimal performance was achieved with a sequence identify cutoff of 50% to remove distant homologs. The new version of DeepSAV exhibits the best performance among standalone predictors of deleterious effects of SAVs. We developed the DBSAV database (http://prodata.swmed.edu/DBSAV) that reports GTS scores of human genes and DeepSAV scores of SAVs in the human proteome, including pathogenic and benign SAVs, population-level SAVs, and all possible SAVs by single nucleotide variations. This database serves as a useful resource for research of human SAVs and their relationships with protein functions and human diseases.


Assuntos
Aminoácidos/genética , Bases de Dados de Proteínas , Variação Genética , Proteoma/genética , Área Sob a Curva , Humanos , Redes Neurais de Computação , Curva ROC
14.
mSystems ; 6(1)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563785

RESUMO

Diverse bacterial pathogens employ effector delivery systems to disrupt vital cellular processes in the host (N. M. Alto and K. Orth, Cold Spring Harbor Perspect Biol 4:a006114, 2012, https://doi.org/10.1101/cshperspect.a006114). The type III secretion system 1 of the marine pathogen Vibrio parahaemolyticus utilizes the sequential action of four effectors to induce a rapid, proinflammatory cell death uniquely characterized by a prosurvival host transcriptional response (D. L. Burdette, M. L. Yarbrough, A Orvedahl, C. J. Gilpin, and K. Orth, Proc Natl Acad Sci USA 105:12497-12502, 2008, https://doi.org/10.1073/pnas.0802773105; N. J. De Nisco, M. Kanchwala, P. Li, J. Fernandez, C. Xing, and K. Orth, Sci Signal 10:eaa14501, 2017, https://doi.org/10.1126/scisignal.aal4501). Herein, we show that this prosurvival response is caused by the action of the channel-forming effector VopQ that targets the host V-ATPase, resulting in lysosomal deacidification and inhibition of lysosome-autophagosome fusion. Recent structural studies have shown how VopQ interacts with the V-ATPase and, while in the ER, a V-ATPase assembly intermediate can interact with VopQ, causing a disruption in membrane integrity. Additionally, we observed that VopQ-mediated disruption of the V-ATPase activates the IRE1 branch of the unfolded protein response (UPR), resulting in an IRE1-dependent activation of ERK1/2 MAPK signaling. We also find that this early VopQ-dependent induction of ERK1/2 phosphorylation is terminated by the VopS-mediated inhibitory AMPylation of Rho GTPase signaling. Since VopS dampens VopQ-induced IRE1-dependent ERK1/2 activation, we propose that IRE1 activates ERK1/2 phosphorylation at or above the level of Rho GTPases. This study illustrates how temporally induced effectors can work as in tandem as agonist/antagonist to manipulate host signaling and reveals new connections between V-ATPase function, UPR, and MAPK signaling.IMPORTANCE Vibrio parahaemolyticus is a seafood-borne pathogen that encodes two type 3 secretion systems (T3SS). The first system, T3SS1, is thought to be maintained in all strains of V. parahaemolyticus to maintain survival in the environment, whereas the second system, T3SS2, is linked to clinical isolates and disease in humans. Here, we found that first system targets evolutionarily conserved signaling systems to manipulate host cells, eventually causing a rapid, orchestrated cells death within 3 h. We have found that the T3SS1 injects virulence factors that temporally manipulate host signaling. Within the first hour of infection, the effector VopQ acts first by activating host survival signals while diminishing the host cell apoptotic machinery. Less than an hour later, another effector, VopS, reverses activation and inhibition of these signaling systems, ultimately leading to death of the host cell. This work provides example of how pathogens have evolved to manipulate the interplay between T3SS effectors to regulate host signaling pathways.

15.
mBio ; 12(1)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563831

RESUMO

Rice blast disease caused by Magnaporthe oryzae is a devastating disease of cultivated rice worldwide. Infections by this fungus lead to a significant reduction in rice yields and threats to food security. To gain better insight into growth and cell death in M. oryzae during infection, we characterized two predicted M. oryzae metacaspase proteins, MoMca1 and MoMca2. These proteins appear to be functionally redundant and can complement the yeast Yca1 homologue. Biochemical analysis revealed that M. oryzae metacaspases exhibited Ca2+-dependent caspase activity in vitro Deletion of both MoMca1 and MoMca2 in M. oryzae resulted in reduced sporulation, delay in conidial germination, and attenuation of disease severity. In addition, the double ΔMomca1mca2 mutant strain showed increased radial growth in the presence of oxidative stress. Interestingly, the ΔMomca1mca2 strain showed an increased accumulation of insoluble aggregates compared to the wild-type strain during vegetative growth. Our findings suggest that MoMca1 and MoMca2 promote the clearance of insoluble aggregates in M. oryzae, demonstrating the important role these metacaspases have in fungal protein homeostasis. Furthermore, these metacaspase proteins may play additional roles, like in regulating stress responses, that would help maintain the fitness of fungal cells required for host infection.IMPORTANCE Magnaporthe oryzae causes rice blast disease that threatens global food security by resulting in the severe loss of rice production every year. A tightly regulated life cycle allows M. oryzae to disarm the host plant immune system during its biotrophic stage before triggering plant cell death in its necrotrophic stage. The ways M. oryzae navigates its complex life cycle remain unclear. This work characterizes two metacaspase proteins with peptidase activity in M. oryzae that are shown to be involved in the regulation of fungal growth and development prior to infection by potentially helping maintain fungal fitness. This study provides new insights into the role of metacaspase proteins in filamentous fungi by illustrating the delays in M. oryzae morphogenesis in the absence of these proteins. Understanding the mechanisms by which M. oryzae morphology and development promote its devastating pathogenicity may lead to the emergence of proper methods for disease control.


Assuntos
Ascomicetos/enzimologia , Ascomicetos/patogenicidade , Caspases/genética , Caspases/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Oryza/microbiologia , Ascomicetos/genética , Ascomicetos/crescimento & desenvolvimento , Caspases/classificação , Biologia Computacional , Regulação Fúngica da Expressão Gênica , Genoma Fúngico , Estresse Oxidativo , Doenças das Plantas/microbiologia , Proteínas de Saccharomyces cerevisiae/genética , Virulência
16.
Proc Natl Acad Sci U S A ; 118(7)2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33568532

RESUMO

We assembled a complete reference genome of Eumaeus atala, an aposematic cycad-eating hairstreak butterfly that suffered near extinction in the United States in the last century. Based on an analysis of genomic sequences of Eumaeus and 19 representative genera, the closest relatives of Eumaeus are Theorema and Mithras We report natural history information for Eumaeus, Theorema, and Mithras Using genomic sequences for each species of Eumaeus, Theorema, and Mithras (and three outgroups), we trace the evolution of cycad feeding, coloration, gregarious behavior, and other traits. The switch to feeding on cycads and to conspicuous coloration was accompanied by little genomic change. Soon after its origin, Eumaeus split into two fast evolving lineages, instead of forming a clump of close relatives in the phylogenetic tree. Significant overlap of the fast evolving proteins in both clades indicates parallel evolution. The functions of the fast evolving proteins suggest that the caterpillars developed tolerance to cycad toxins with a range of mechanisms including autophagy of damaged cells, removal of cell debris by macrophages, and more active cell proliferation.


Assuntos
Borboletas/genética , Cycadopsida/toxicidade , Evolução Molecular , Comportamento Alimentar , Animais , Borboletas/classificação , Borboletas/fisiologia , Especiação Genética , Genoma de Inseto , Filogenia
17.
J Mol Biol ; 433(4): 166788, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33387532

RESUMO

The Rossmann-like fold is the most prevalent and diversified doubly-wound superfold of ancient evolutionary origin. Rossmann-like domains are present in a variety of metabolic enzymes and are capable of binding diverse ligands. Discerning evolutionary relationships among these domains is challenging because of their diverse functions and ancient origin. We defined a minimal Rossmann-like structural motif (RLM), identified RLM-containing domains among known 3D structures (20%) and classified them according to their homologous relationships. New classifications were incorporated into our Evolutionary Classification of protein Domains (ECOD) database. We defined 156 homology groups (H-groups), which were further clustered into 123 possible homology groups (X-groups). Our analysis revealed that RLM-containing proteins constitute approximately 15% of the human proteome. We found that disease-causing mutations are more frequent within RLM domains than within non-RLM domains of these proteins, highlighting the importance of RLM-containing proteins for human health.


Assuntos
Motivos de Aminoácidos , Modelos Moleculares , Conformação Proteica , Proteínas/química , Sítios de Ligação , Evolução Biológica , Bases de Dados de Proteínas , Humanos , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Domínios Proteicos , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas/genética , Proteínas/metabolismo
18.
Genet Med ; 23(5): 900-908, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33473208

RESUMO

PURPOSE: Neurodevelopmental disabilities are common and genetically heterogeneous. We identified a homozygous variant in the gene encoding UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway of protein modification. UFSP2 variants are implicated in autosomal dominant skeletal dysplasias, but not neurodevelopmental disorders. Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy. We describe the clinical consequences of this variant and its effect on UFMylation. METHODS: Exome sequencing was used to detect potentially pathogenic variants and identify shared regions of homozygosity. Immunoblotting assessed protein expression and post-translational modifications in patient-derived fibroblasts. RESULTS: The variant (c.344T>A; p.V115E) is rare and alters a conserved residue in UFSP2. Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than UFMylation. Reconstituting patient-derived fibroblasts with wild-type UFSP2 reduced UFMylation marks. Analysis of UFSP2's structure indicated that variants observed in skeletal disorders localize to the catalytic domain, whereas V115 resides in an N-terminal domain possibly involved in substrate binding. CONCLUSION: Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy.


Assuntos
Epilepsia , Transtornos do Neurodesenvolvimento , Osteocondrodisplasias , Criança , Epilepsia/genética , Homozigoto , Humanos , Transtornos do Neurodesenvolvimento/genética , Sequenciamento Completo do Exoma
19.
Mol Biol Evol ; 38(5): 2166-2176, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33502509

RESUMO

Centuries of zoological studies have amassed billions of specimens in collections worldwide. Genomics of these specimens promises to reinvigorate biodiversity research. However, because DNA degrades with age in historical specimens, it is a challenge to obtain genomic data for them and analyze degraded genomes. We developed experimental and computational protocols to overcome these challenges and applied our methods to resolve a series of long-standing controversies involving a group of butterflies. We deduced the geographical origins of several historical specimens of uncertain provenance that are at the heart of these debates. Here, genomics tackles one of the greatest problems in zoology: countless old specimens that serve as irreplaceable embodiments of species concepts cannot be confidently assigned to extant species or population due to the lack of diagnostic morphological features and clear documentation of the collection locality. The ability to determine where they were collected will resolve many on-going disputes. More broadly, we show the utility of applying genomics to historical museum specimens to delineate the boundaries of species and populations, and to hypothesize about genotypic determinants of phenotypic traits.


Assuntos
Borboletas/genética , DNA Antigo/análise , Genômica/métodos , Adaptação Biológica/genética , Altitude , Animais , Pigmentação/genética
20.
Zootaxa ; 4877(3): zootaxa.4877.3.3, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311178

RESUMO

We studied wing pattern characters to distinguish closely related sympatric species Papilio zelicaon Lucas, 1852 and Papilio polyxenes Fabricius, 1775 in Southern California, and developed a morphometric method based on the ventral black postmedian band. Application of this method to the holotype of Papilio [Zolicaon variety] Coloro W. G. Wright, 1905, the name currently applied to the P. polyxenes populations, revealed that it is a P. zelicaon specimen. The name for western US polyxenes subspecies thus becomes Papilio polyxenes rudkini (F. R. Chermock, 1981), reinstated status, and we place coloro as a junior subjective synonym of P. zelicaon. Furthermore, we sequenced mitochondrial DNA COI barcodes of rudkini and coloro holotypes and compared them with those of polyxenes and zelicaon specimens, confirming rudkini as polyxenes and coloro as zelicaon.


Assuntos
Borboletas , Animais , Sequência de Bases , Borboletas/genética , California , DNA Mitocondrial , Asas de Animais
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