image: schematic diagrams for protein sequences
Credit: JING YANG
A recent study published in Magnetic Resonance Letters has revealed for the first time the interaction mechanism between the mitochondrial proteins HAX1 and CLPB, filling the research gap between these two key proteins in the field of structural dynamics and functional association. By integrating multiple biophysical techniques, the research team based in Hefei, China, revealed the high-affinity binding properties between the two and their structural basis, which provides new research perspectives for understanding diseases related to abnormal mitochondrial function.
HAX1 and CLPB: from structural differences to functional synergy
HAX1 (HCLS1-associated protein X-1) is a multifunctional mitochondrial protein involved in key processes such as apoptosis, mRNA processing and calcium homeostasis regulation. However, its intrinsically disordered structure has long hindered the understanding of its molecular mechanism, and CLPB, a mitochondrial protein with ATPase activity, has been shown to regulate deaggregase activity through dynamic assembly (e.g., heptamer-to-hexamer conformational transitions). In the present study, CLPB was found to exhibit a typical a-helical folded structure, whereas HAX1 exhibits a highly dynamic disordered conformation. This structural complementarity may provide a physical basis for the functional synergy between the two.
High-precision technique reveals binding dynamics
The binding affinity of HAX1 and CLPB was accurately determined using nuclear magnetic resonance (NMR) technology. Multi-protein complex formed by the two has a dissociation constant (Kd) at the low micro-molar level, suggesting that the interaction is stable and efficient. In addition, molecular exclusion chromatography and dynamic light scattering experiments further confirmed that the formation of the complex relies on the specific recognition between the disordered region of HAX1 and the helical structural domain of CLPB.
Expert Opinion and Research Implications
“This study lays a foundation for the study of the energetics and dynamic behavior of the HAX1-CLPB complex,” says corresponding author Prof Junfeng Wang. ”Going forward, we can resolve the three-dimensional structure of the complex with the help of cryo-electron microscopy and other techniques to reveal its molecular mechanism in the disease-related pathways.”
Aberrant expression of HAX1 is associated with a variety of diseases, such as defective angiogenesis and immune cell apoptosis in nasopharyngeal carcinoma metastasis, while mutations in CLPB are closely associated with genetic diseases such as mitochondrial encephalomyopathy. By elucidating the structural framework of the interaction between the two, this study provides new ideas for developing targeted therapeutic strategies against this complex.
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Contact the author: Junfeng Wang, High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China junfeng@hmfl.ac.cn
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Journal
Magnetic Resonance Letters
Method of Research
Experimental study
Subject of Research
Not applicable
Article Title
Biophysical and NMR analysis reveals binding affinity between HAX1 and CLPB proteins
COI Statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.