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Endocytotic routes of cobra cardiotoxins depend on spatial distribution of positively charged and hydrophobic domains to target distinct types of sulfated glycoconjugates on cell surface
- Source :
- The Journal of biological chemistry. 289(29)
- Publication Year :
- 2014
-
Abstract
- Cobra cardiotoxins (CTX) are a family of three-fingered basic polypeptides known to interact with diverse targets such as heparan sulfates, sulfatides, and integrins on cell surfaces. After CTX bind to the membrane surface, they are internalized to intracellular space and exert their cytotoxicity via an unknown mechanism. By the combined in vitro kinetic binding, three-dimensional x-ray structure determination, and cell biology studies on the naturally abundant CTX homologues from the Taiwanese cobra, we showed that slight variations on the spatial distribution of positively charged or hydrophobic domains among CTX A2, A3, and A4 could lead to significant changes in their endocytotic pathways and action mechanisms via distinct sulfated glycoconjugate-mediated processes. The intracellular locations of these structurally similar CTX after internalization are shown to vary between the mitochondria and lysosomes via either dynamin2-dependent or -independent processes with distinct membrane cholesterol sensitivity. Evidence is presented to suggest that the shifting between the sulfated glycoconjugates as distinct targets of CTX A2, A3, and A4 might play roles in the co-evolutionary arms race between venomous snake toxins to cope with different membrane repair mechanisms at the cellular levels. The sensitivity of endocytotic routes to the spatial distribution of positively charged or hydrophobic domains may provide an explanation for the diverse endocytosis pathways of other cell-penetrating basic polypeptides.
- Subjects :
- Models, Molecular
Glycoconjugate
media_common.quotation_subject
Integrin
Molecular Sequence Data
Static Electricity
Cobra Cardiotoxin Proteins
Glycobiology and Extracellular Matrices
CHO Cells
Biology
Endocytosis
Crystallography, X-Ray
Biochemistry
complex mixtures
Cell Line
Cell membrane
Evolution, Molecular
chemistry.chemical_compound
Cricetulus
Cricetinae
medicine
Animals
Protein Interaction Domains and Motifs
Amino Acid Sequence
Elapidae
Internalization
Molecular Biology
media_common
chemistry.chemical_classification
Binding Sites
Cell Membrane
Cell Biology
Heparan sulfate
respiratory system
Rats
medicine.anatomical_structure
chemistry
Structural Homology, Protein
Biophysics
biology.protein
behavior and behavior mechanisms
Heparitin Sulfate
human activities
Glycoconjugates
Hydrophobic and Hydrophilic Interactions
Intracellular
Subjects
Details
- ISSN :
- 1083351X
- Volume :
- 289
- Issue :
- 29
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....5171edfb4d989d5c6c1eab13cef75f1c