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Identification of a ?-helical molten globule intermediate and structural characterization of ?-cardiotoxin, an all ?-sheet protein isolated from the venom of Ophiophagus hannah (king cobra).

ABSTRACT: ?-Cardiotoxin is a novel member of the snake venom three-finger toxin (3FTX) family. This is the first exogenous protein to antagonize ?-adrenergic receptors and thereby causing reduction in heart rates (bradycardia) when administered into animals, unlike the conventional cardiotoxins as reported earlier. 3FTXs are stable all ?-sheet peptides with 60-80 amino acid residues. Here, we describe the three-dimensional crystal structure of ?-cardiotoxin together with the identification of a molten globule intermediate in the unfolding pathway of this protein. In spite of the overall structural similarity of this protein with conventional cardiotoxins, there are notable differences observed at the loop region and in the charge distribution on the surface, which are known to be critical for cytolytic activity of cardiotoxins. The molten globule intermediate state present in the thermal unfolding pathway of ?-cardiotoxin was however not observed during the chemical denaturation of the protein. Interestingly, circular dichroism (CD) and NMR studies revealed the presence of ?-helical secondary structure in the molten globule intermediate. These results point to substantial conformational plasticity of ?-cardiotoxin, which might aid the protein in responding to the sometimes conflicting demands of structure, stability, and function during its biological lifetime.

SUBMITTER: Roy A

PROVIDER: S-EPMC6459992 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Identification of a α-helical molten globule intermediate and structural characterization of β-cardiotoxin, an all β-sheet protein isolated from the venom of Ophiophagus hannah (king cobra).

Roy Amrita A Qingxiang Sun S Alex Chapeaurouge C Rajagopalan Nandhakishore N Jobichen Chacko C Sivaraman J J Kini R Manjunatha RM

Protein science : a publication of the Protein Society 20190404 5

β-Cardiotoxin is a novel member of the snake venom three-finger toxin (3FTX) family. This is the first exogenous protein to antagonize β-adrenergic receptors and thereby causing reduction in heart rates (bradycardia) when administered into animals, unlike the conventional cardiotoxins as reported earlier. 3FTXs are stable all β-sheet peptides with 60-80 amino acid residues. Here, we describe the three-dimensional crystal structure of β-cardiotoxin together with the identification of a molten glo ...[more]

PMID: 30891862

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Project description:BackgroundThe king cobra (Ophiophagus hannah) is widely distributed throughout many parts of Asia. This study aims to investigate the complexity of Malaysian Ophiophagus hannah (MOh) venom for a better understanding of king cobra venom variation and its envenoming pathophysiology. The venom gland transcriptome was investigated using the Illumina HiSeq™ platform, while the venom proteome was profiled by 1D-SDS-PAGE-nano-ESI-LCMS/MS.ResultsTranscriptomic results reveal high redundancy of toxin transcripts (3357.36 FPKM/transcript) despite small cluster numbers, implying gene duplication and diversification within restricted protein families. Among the 23 toxin families identified, three-finger toxins (3FTxs) and snake-venom metalloproteases (SVMPs) have the most diverse isoforms. These 2 toxin families are also the most abundantly transcribed, followed in descending order by phospholipases A2 (PLA2s), cysteine-rich secretory proteins (CRISPs), Kunitz-type inhibitors (KUNs), and L-amino acid oxidases (LAAOs). Seventeen toxin families exhibited low mRNA expression, including hyaluronidase, DPP-IV and 5'-nucleotidase that were not previously reported in the venom-gland transcriptome of a Balinese O. hannah. On the other hand, the MOh proteome includes 3FTxs, the most abundantly expressed proteins in the venom (43 % toxin sbundance). Within this toxin family, there are 6 long-chain, 5 short-chain and 2 non-conventional 3FTx. Neurotoxins comprise the major 3FTxs in the MOh venom, consistent with rapid neuromuscular paralysis reported in systemic envenoming. The presence of toxic enzymes such as LAAOs, SVMPs and PLA2 would explain tissue inflammation and necrotising destruction in local envenoming. Dissimilarities in the subtypes and sequences between the neurotoxins of MOh and Naja kaouthia (monocled cobra) are in agreement with the poor cross-neutralization activity of N. kaouthia antivenom used against MOh venom. Besides, the presence of cobra venom factor, nerve growth factors, phosphodiesterase, 5'-nucleotidase, and DPP-IV in the venom proteome suggests its probable hypotensive action in subduing prey.ConclusionThis study reports the diversity and abundance of toxins in the venom of the Malaysian king cobra (MOh). The results correlate with the pathophysiological actions of MOh venom, and dispute the use of Naja cobra antivenoms to treat MOh envenomation. The findings also provide a deeper insight into venom variations due to geography, which is crucial for the development of a useful pan-regional antivenom.

Dataset Information

Identification of a ?-helical molten globule intermediate and structural characterization of ?-cardiotoxin, an all ?-sheet protein isolated from the venom of Ophiophagus hannah (king cobra).

Publications

Identification of a α-helical molten globule intermediate and structural characterization of β-cardiotoxin, an all β-sheet protein isolated from the venom of Ophiophagus hannah (king cobra).

Similar Datasets

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