Tracing the Evolutionary History of the CAP Superfamily of Proteins Using Amino Acid Sequence Homology and Conservation of Splice Sites

Abraham, Anup; Chandler, Douglas E.

doi:10.1007/s00239-017-9813-9

Cited by 24 publications

(22 citation statements)

References 117 publications

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“…The CAP superfamily proteins are well distributed in all organisms, where they display a variety of functions [98]. This superfamily includes three major groups of proteins: cysteine-rich secretory proteins (CRISP), antigen or allergen proteins from arthropod venoms, and pathogenesis-related proteins from plants (PR) [99]. The CRISP proteins and antigen/allergen proteins have been described in venoms [100].…”

Section: Resultsmentioning

confidence: 99%

Dissecting Toxicity: The Venom Gland Transcriptome and the Venom Proteome of the Highly Venomous Scorpion Centruroides limpidus (Karsch, 1879)

Cid-Uribe

Meneses

Batista

et al. 2019

Toxins

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Venom glands and soluble venom from the Mexican scorpion Centruroides limpidus (Karsch, 1879) were used for transcriptomic and proteomic analyses, respectively. An RNA-seq was performed by high-throughput sequencing with the Illumina platform. Approximately 80 million reads were obtained and assembled into 198,662 putative transcripts, of which 11,058 were annotated by similarity to sequences from available databases. A total of 192 venom-related sequences were identified, including Na+ and K+ channel-acting toxins, enzymes, host defense peptides, and other venom components. The most diverse transcripts were those potentially coding for ion channel-acting toxins, mainly those active on Na+ channels (NaScTx). Sequences corresponding to β- scorpion toxins active of K+ channels (KScTx) and λ-KScTx are here reported for the first time for a scorpion of the genus Centruroides. Mass fingerprint corroborated that NaScTx are the most abundant components in this venom. Liquid chromatography coupled to mass spectometry (LC-MS/MS) allowed the identification of 46 peptides matching sequences encoded in the transcriptome, confirming their expression in the venom. This study corroborates that, in the venom of toxic buthid scorpions, the more abundant and diverse components are ion channel-acting toxins, mainly NaScTx, while they lack the HDP diversity previously demonstrated for the non-buthid scorpions. The highly abundant and diverse antareases explain the pancreatitis observed after envenomation by this species.

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Section: Resultsmentioning

confidence: 99%

Dissecting Toxicity: The Venom Gland Transcriptome and the Venom Proteome of the Highly Venomous Scorpion Centruroides limpidus (Karsch, 1879)

Cid-Uribe

Meneses

Batista

et al. 2019

Toxins

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“…For several CAP proteins, it has been shown that metal binding is critical for specific functions [14–17] and that two highly conserved histidines of the CAP tetrad co-ordinate Zn 2+ or other divalent metal ions. GAPR-1 consists almost exclusively of a CAP domain and the GAPR-1 subfamily was recently described to be the earliest evolutionary ancestor within the CAP superfamily [18]. GAPR-1 is therefore a suitable model protein to study the CAP domain structure–function relationship.…”

Section: Introductionmentioning

confidence: 99%

Zinc binding regulates amyloid-like aggregation of GAPR-1

et al. 2019

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Members of the CAP superfamily (Cysteine-rich secretory proteins, Antigen 5, and Pathogenesis-related 1 proteins) are characterized by the presence of a CAP domain that is defined by four sequence motifs and a highly conserved tertiary structure. A common structure–function relationship for this domain is hitherto unknown. A characteristic of several CAP proteins is their formation of amyloid-like structures in the presence of lipids. Here we investigate the structural modulation of Golgi-Associated plant Pathogenesis Related protein 1 (GAPR-1) by known interactors of the CAP domain, preceding amyloid-like aggregation. Using isothermal titration calorimetry (ITC), we demonstrate that GAPR-1 binds zinc ions. Zn2+ binding causes a slight but significant conformational change as revealed by CD, tryptophan fluorescence, and trypsin digestion. The Zn2+-induced conformational change was required for the formation of GAPR-1 oligomers and amyloid-like assemblies in the presence of heparin, as shown by ThT fluorescence and TEM. Molecular dynamics simulations show binding of Zn2+ to His54 and His103. Mutation of these two highly conserved residues resulted in strongly diminished amyloid-like aggregation. Finally, we show that proteins from the cysteine-rich secretory protein (CRISP) subfamily are also able to form ThT-positive structures in vitro in a heparin- and Zn2+-dependent manner, suggesting that oligomerization regulated by metal ions could be a common structural property of the CAP domain.

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“…GAPR-1 is the most ancient CAP subfamily member in vertebrates that evolved from the CAP/PR domain in bacteria 1,12 . These one-domain proteins evolved in invertebrates and mammals into proteins with two domains, connected via a hinge region.…”

Section: Introductionmentioning

confidence: 99%

Metal ions and redox balance regulate distinct amyloid-like aggregation pathways of GAPR-1

Sheng

Olrichs

Geerts

et al. 2019

Sci Rep

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Members of the CAP superfamily (Cysteine-rich secretory proteins, Antigen 5, and Pathogenesis-Related 1 proteins) are characterized by the presence of a structurally conserved CAP domain. The common structure-function relationship of this domain is still poorly understood. In this study, we unravel specific molecular mechanisms modulating the quaternary structure of the mammalian CAP protein GAPR-1 (Golgi-Associated plant Pathogenesis-Related protein 1). Copper ions are shown to induce a distinct amyloid-like aggregation pathway of GAPR-1 in the presence of heparin. This involves an immediate shift from native multimers to monomers which are prone to form amyloid-like fibrils. The Cu2+-induced aggregation pathway is independent of a conserved metal-binding site and involves the formation of disulfide bonds during the nucleation process. The elongation process occurs independently of the presence of Cu2+ ions, and amyloid-like aggregation can proceed under oxidative conditions. In contrast, the Zn2+-dependent aggregation pathway was found to be independent of cysteines and was reversible upon removal of Zn2+ ions. Together, our results provide insight into the regulation of the quaternary structure of GAPR-1 by metal ions and redox homeostasis with potential implications for regulatory mechanisms of other CAP proteins.

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Tracing the Evolutionary History of the CAP Superfamily of Proteins Using Amino Acid Sequence Homology and Conservation of Splice Sites

Cited by 24 publications

References 117 publications

Dissecting Toxicity: The Venom Gland Transcriptome and the Venom Proteome of the Highly Venomous Scorpion Centruroides limpidus (Karsch, 1879)

Dissecting Toxicity: The Venom Gland Transcriptome and the Venom Proteome of the Highly Venomous Scorpion Centruroides limpidus (Karsch, 1879)

Zinc binding regulates amyloid-like aggregation of GAPR-1

Metal ions and redox balance regulate distinct amyloid-like aggregation pathways of GAPR-1

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