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Identification of a novel effector domain of BIN1 for cancer suppression
Greta L Lundgaard1, Natae E Daniels, Slovénie Pyndiah
1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, USA.
Insights
Bridging integrator 1 (BIN1) has a novel domain that suppresses cancer independently of c-MYC. This MYC-independent domain (MID) resides in the BIN1 BAR region and inhibits cancer growth.
Area of Science:
- Molecular Biology
- Cancer Research
- Protein Structure and Function
Background:
- Bridging integrator 1 (BIN1) is a nucleocytoplasmic adaptor protein exhibiting tumor suppressor characteristics.
- BIN1 interacts with and inhibits the c-MYC transcription factor via its MYC-binding domain (MBD).
- Previous studies indicated that the MBD is not essential for BIN1's growth-arresting function.
Purpose of the Study:
- To investigate the existence and function of a MYC-independent effector domain (MID) within BIN1 for cancer suppression.
- To identify the specific region of BIN1 responsible for MYC-independent cancer growth inhibition.
Main Methods:
- Limited trypsin digestion of full-length human BIN1 protein.
- Analysis of digested peptides using Edman sequencing and mass spectrometry.
- Computational analysis to predict structural motifs (coiled-coil) within identified peptides.
- Subcellular localization studies and cancer growth inhibition assays.
Main Results:
- A trypsin-resistant peptide (amino acids 146-268) from the BIN1 BAR region was identified.
- This peptide contains predicted coiled-coil motifs, suggesting a role in protein structure and function.
- The BIN1 BAR peptide, similar to MBD-deleted BIN1, localized to the cytoplasm and inhibited cancer growth irrespective of c-MYC activity.
Conclusions:
- The identified BIN1 BAR peptide represents a novel MYC-independent effector domain (MID).
- BIN1 functions as a cancer suppressor through this MID, independent of its interaction with c-MYC.
- This discovery offers new insights into BIN1's tumor suppressor mechanisms and potential therapeutic targets.
Abstract:
Bridging integrator 1 (BIN1) is a nucleocytoplasmic adaptor protein with tumor suppressor properties. The protein interacts with and inhibits the c-MYC transcription factor through the BIN1 MYC-binding domain (MBD). However, in vitro colony formation assays have clearly demonstrated that the MBD is not essential for BIN1-mediated growth arrest. We hypothesized that BIN1 contains a MYC-independent effector domain (MID) for cancer suppression. Because a functionally unique domain frequently contains a distinct structure, the human full-length BIN1 protein was subjected to limited trypsin digestion and the digested peptides were analyzed with Edman sequencing and mass spectrometry. We identified a trypsin-resistant peptide that corresponds to amino acids 146-268 of BIN1. It encompassed part of the BAR region, a putative effector region of BIN1. Computational analysis predicted that the peptide is very likely to exhibit coiled-coil motifs, implying a potential role for this region in sustaining the BIN1 structure and function. Like MBD-deleted BIN1, the trypsin-resistant peptide of BIN1 was predominantly present in the cytoplasm and was sufficient to inhibit cancer growth, regardless of dysregulated c-MYC activity. Our results suggest that the coiled-coil BIN1 BAR peptide encodes a novel BIN1 MID domain, through which BIN1 acts as a MYC-independent cancer suppressor.
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