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Mass Spectrometry Investigation of Some ATP-Binding Cassette (ABC) Proteins
Marco Agostini1, Pietro Traldi1, Mahmoud Hamdan1
1Corso Stati Uniti 4, Istituto di Ricerca Pediatrica Città della Speranza, 35100 Padova, Italy.
Abstract:
Drug resistance remains one of the main causes of poor outcome in cancer therapy. It is also becoming evident that drug resistance to both chemotherapy and to antibiotics is driven by more than one mechanism. So far, there are at least eight recognized mechanisms behind such resistance. In this review, we choose to discuss one of these mechanisms, which is known to be partially driven by a class of transmembrane proteins known as ATP-binding cassette (ABC) transporters. In normal tissues, ABC transporters protect the cells from the toxic effects of xenobiotics, whereas in tumor cells, they reduce the intracellular concentrations of anticancer drugs, which ultimately leads to the emergence of multidrug resistance (MDR). A deeper understanding of the structures and the biology of these proteins is central to current efforts to circumvent resistance to both chemotherapy, targeted therapy, and antibiotics. Understanding the biology and the function of these proteins requires detailed structural and conformational information for this class of membrane proteins. For many years, such structural information has been mainly provided by X-ray crystallography and cryo-electron microscopy. More recently, mass spectrometry-based methods assumed an important role in the area of structural and conformational characterization of this class of proteins. The contribution of this technique to structural biology has been enhanced by its combination with liquid chromatography and ion mobility, as well as more refined labelling protocols and the use of more efficient fragmentation methods, which allow the detection and localization of labile post-translational modifications. In this review, we discuss the contribution of mass spectrometry to efforts to characterize some members of the ATP-binding cassette (ABC) proteins and why such a contribution is relevant to efforts to clarify the link between the overexpression of these proteins and the most widespread mechanism of chemoresistance.
Insights
Drug resistance in cancer and infections is a major challenge. ATP-binding cassette (ABC) transporters contribute to this resistance, and mass spectrometry is key to understanding their structure and function.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Drug resistance, driven by multiple mechanisms, significantly impacts cancer and antibiotic therapy outcomes.
- ATP-binding cassette (ABC) transporters, crucial for xenobiotic transport, mediate multidrug resistance (MDR) in tumor cells by reducing intracellular drug concentrations.
Purpose of the Study:
- To review the role of ATP-binding cassette (ABC) transporters in drug resistance.
- To highlight the contribution of mass spectrometry to understanding the structure and function of ABC proteins for overcoming resistance.
Main Methods:
- Review of existing literature on ABC transporters and drug resistance mechanisms.
- Focus on the application of mass spectrometry-based methods for structural and conformational characterization of ABC proteins.
- Integration of mass spectrometry with techniques like liquid chromatography and ion mobility.
Main Results:
- ABC transporters are a significant mechanism contributing to multidrug resistance (MDR).
- Mass spectrometry, especially when coupled with other techniques, provides crucial structural and conformational insights into ABC proteins.
- This understanding is vital for developing strategies to circumvent drug resistance.
Conclusions:
- Mass spectrometry is an increasingly important tool for characterizing ABC transporters.
- Elucidating the structure and function of ABC proteins is essential for addressing chemoresistance and antibiotic resistance.
- Further research into ABC transporter biology using advanced mass spectrometry techniques can guide the development of novel therapeutic strategies.
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