How Does Lactylation Influence Protein–Molecule Interactions?
- Modulation of recognition domains: Lactylation may alter the ability of structural motifs such as SH2 or bromodomains to recognize phosphorylated or acetylated marks.
- Influence on multiprotein complex assembly: The modification can determine whether specific subunits bind stably within protein complexes.
- Alteration of subcellular localization and binding preferences: Lactylation may affect a protein’s affinity for certain organelle membranes, nucleic acid structures, or cytoskeletal components.
- Proteomic profiling of lactylation modifications (qualitative, quantitative, and site annotation)
- Integrated PTM enrichment and detection (lactylation, acetylation, phosphorylation, ubiquitination, etc.)
- Validation of protein binding activity
- Structural modeling and systems-level analysis of modifications
Protein–molecule interactions represent fundamental biological processes that underlie essential cellular functions such as signal transduction, transcriptional regulation, substrate recognition, and macromolecular complex assembly. Post-translational modifications (PTMs), which covalently modify amino acid residues, play pivotal roles in modulating the three-dimensional conformation, chemical properties, and binding capacities of proteins. As a recently identified type of PTM, lysine lactylation (Kla) has emerged as a potential mechanism for regulating protein–molecule interactions. This modification may alter the binding properties of proteins with DNA, RNA, small molecules, or other proteins, thereby influencing cell fate determination, metabolic regulation, and disease progression.
How Does Lactylation Alter Protein–Molecule Interactions Capacity at the Structural Level?
1. Charge Neutralization and Its Effect on Electrostatic Interactions
Lysine lactylation neutralizes the ε-amino group’s positive charge, converting the residue from a cationic to a neutral state. This shift markedly reduces electrostatic attractions, particularly those between proteins and negatively charged molecules such as DNA, RNA, or phosphorylated proteins. Disruption or reorganization of electrostatic networks may consequently diminish the protein’s original binding selectivity or confer new binding preferences.
2. Conformational Rearrangement and Interface Remodeling
The incorporation of a polar acyl group during lysine lactylation introduces steric hindrance within the side chain. When the modified residue resides at a molecular interface or within a critical structural domain, lactylation can trigger local conformational rearrangements, altering the geometry of the binding interface and thereby modulating binding affinity or specificity. Moreover, such conformational changes may expose or obscure additional functional residues, generating coordinated effects across multiple regulatory layers.
3. Reorganization of Hydrogen-Bonding Networks and Hydrophobic Surface Distribution
The hydroxyl group of the lactyl moiety can act as either a hydrogen-bond donor or acceptor, facilitating the formation of new hydrogen-bond networks. These additional interactions may stabilize certain binding interfaces or disrupt pre-existing critical hydrogen bonds. Furthermore, lactylation may alter the balance of hydrophobic and hydrophilic surface regions on the protein, thereby influencing its interactions with small substrates, cofactors, or protein partners.
A Systems Perspective: The Role of Lactylation in Protein Interaction Networks
From a systems biology standpoint, protein–molecule interactions form intricate and dynamic networks (interactomes) rather than simple one-to-one associations. The introduction of lactylation can induce cascading effects at multiple organizational levels:
Hence, the role of lactylation in protein function extends far beyond serving as a simple on–off switch or molecular tag. Instead, it functions as a finely tuned regulatory mediator that integrates structural, chemical, and spatial cues within protein interaction networks.
Experimental Strategies: How to Investigate the Effect of Lactylation on Protein Binding Behavior?
Experimental approaches for assessing the impact of lactylation on protein–molecule binding typically encompass the following levels:
1. Site Identification and Quantitative Profiling
High-resolution mass spectrometry combined with Kla-specific antibody enrichment enables the identification of lactylation sites and quantitative evaluation of modification levels, providing the foundation for downstream functional analyses.
2. Evaluation of Binding Activity
By employing site-directed mutagenesis (e.g., K→Q or K→E substitutions to mimic lactylation), subsequent binding assays such as pull-down, EMSA, Co-IP, SPR, or ITC can be used to measure changes in affinity and interaction strength.
3. Structural Modeling and Molecular Dynamics Simulations
Molecular modeling and dynamics simulations can predict the conformational rearrangements and interface adaptations induced by lactylation, offering mechanistic insights into how this modification governs binding behavior.
Technical Support from MtoZ Biolabs
MtoZ Biolabs offers an integrated, high-precision omics platform dedicated to post-translational modification studies, providing comprehensive research services including:
Through high-sensitivity mass spectrometry and integrated bioinformatics analysis, MtoZ Biolabs assists researchers in systematically elucidating the regulatory roles of lactylation in protein function, particularly in the modulation of protein–molecule interactions. The study of lactylation is transitioning from the preliminary exploration of its existence toward a mechanistic understanding of its functional implications. In the context of protein–molecule interactions, the structural, electrostatic, and affinity alterations triggered by lactylation may hold the key to decoding complex regulatory networks. Moving forward, lactylation will likely become a central focus for uncovering protein functional diversity and for targeting the dynamic regulation of protein interactions. MtoZ Biolabs remains committed to advancing this field through high-quality omics data and robust functional validation support.
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