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Peptide LIQ Promotes Cell Protection against Zinc-Induced Cytotoxicity through Microtubule Stabilization
Sina Pejman1, Gholamhossein Riazi1, Shahriar Pooyan1,2
1Institute of Biochemistry and Biophysics , University of Tehran , Tehran , Iran.
Abstract:
Stability of the microtubule protein (MTP) network required for its physiological functions is disrupted in the course of neurodegenerative disorders. Thus, the design of novel therapeutic approaches for microtubule stabilization is a focus of intensive study. Dynamin-related protein-1 (Drp1) is a guanosine triphosphatase (GTPase), which plays a prevailing role in mitochondrial fission. Several isoforms of Drp1 have been identified, of which one of these isoforms (Drp1-x01) has been previously described with MTP stabilizing activity. Here, we synthesized peptide LIQ, an 11-amino-acid peptide derived from the Drp1-x01 isoform, and reported that LIQ could induce tubulin assembly in vitro. Using a Stern-Volmer plot and continuous variation method, we proposed one binding site on tubulin for this peptide. Interestingly, FRET experiment and docking studies showed that LIQ binds the taxol-binding site on β-tubulin. Furthermore, circular dichroism (CD) spectroscopy and 8-anilino-1-naphthalenesulfonic acid (ANS) assay provided data on tubulin structural changes upon LIQ binding that result in formation of more stable tubulin dimers. Flow cytometry analysis and fluorescence microscopy displayed that cellular internalization of 5-FAM-labeled LIQ is attributed to a mechanism that mostly involves endocytosis. In addition, LIQ promoted polymerization of tubulin and stabilized MTP in primary astroglia cells and also protected these cells against zinc toxicity. This excellent feature of cellular neuroprotection by LIQ provides a promising therapeutic approach for neurodegenerative diseases.
Insights
Researchers developed peptide LIQ, derived from Dynamin-related protein-1 (Drp1), to stabilize microtubule protein (MTP) networks. This peptide promotes tubulin assembly and offers neuroprotection, showing promise for treating neurodegenerative diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Microtubule protein (MTP) network stability is crucial for cellular function and is often compromised in neurodegenerative disorders.
- Dynamin-related protein-1 (Drp1) is involved in mitochondrial fission, with specific isoforms exhibiting MTP-stabilizing properties.
Purpose of the Study:
- To synthesize and characterize a novel peptide (LIQ) derived from a Drp1 isoform for its potential to stabilize MTP networks.
- To investigate the mechanism of LIQ's interaction with tubulin and its cellular effects.
Main Methods:
- Synthesis of peptide LIQ from Drp1-x01 isoform.
- In vitro tubulin assembly assays, Stern-Volmer plots, and continuous variation method to determine binding kinetics.
- Förster Resonance Energy Transfer (FRET) and molecular docking to identify the binding site.
- Circular dichroism (CD) spectroscopy and ANS assay for tubulin structural analysis.
- Flow cytometry and fluorescence microscopy for cellular uptake studies.
- Assessment of MTP stabilization and neuroprotection in primary astroglia cells.
Main Results:
- Peptide LIQ induced tubulin assembly in vitro and binds to the taxol-binding site on β-tubulin.
- LIQ binding induced structural changes in tubulin, leading to more stable tubulin dimers.
- Cellular internalization of LIQ primarily occurs via endocytosis.
- LIQ promoted tubulin polymerization and MTP stabilization in astroglia cells, conferring protection against zinc toxicity.
Conclusions:
- Peptide LIQ, derived from Drp1-x01, effectively stabilizes microtubule networks by promoting tubulin assembly and dimer stability.
- LIQ demonstrates cellular neuroprotective properties, suggesting its potential as a therapeutic agent for neurodegenerative diseases.
