Functionally Constrained Human Proteins Show Resilience Against Mutational Instability
Recent research uncovers how specific proteins within humans resist destabilizing mutations caused by amino acid substitutions, providing new insight on genetic disorders.
Missense mutations, alterations where one amino acid is replaced by another, often lead to genetic diseases by destabilizing protein structures. Understanding how some proteins withstand these changes could be pivotal in diagnosing and treating various genetic disorders.
A study published in Nature Communications investigates the relationship between amino acid substitutions and protein stability, highlighting the resilience of functionally constrained proteins. These proteins, which perform pivotal roles within cellular functions, are less susceptible to significant stability changes caused by mutations. The research reveals the mechanisms behind this resilience, which could shed light on the pathways of genetic diseases.
The researchers quantified potential disruptions of protein stability caused by amino acid substitutions using the MAESTRO tool to compute changes represented as ΔΔG values. These stability changes are measured by the difference between the original (native) and altered (mutant) states of proteins. Notably, the study confirms the expectation: the most functionally constrained proteins, categorized by their functional constraints, exhibited narrower ranges of stability variation when subjected to missense mutations.
According to the findings, constrained proteins show smaller stability effects from missense mutations primarily due to greater inherent disorder and increased B-factors—indicating flexibility and stability variations within their structured regions. This intrinsic disorder among functionally constrained proteins allows them to accommodate changes without significant functional consequences, meaning these proteins fare productively even when subjected to potential destabilizing mutations.
Indeed, the researchers indicated there is roughly five times more missense variation with significant stability effects compared to unequivocal loss-of-function mutations found within therapeutic targets. Specifically, there were more observed disruptive stability variations than traditional loss-of-function (LoF) variants within human genes. The study also calculated the false-discovery rate (FDR) for categorizing potentially benign variants, finding the FDR rate for Disruption-of-Stability (DoS) variants being labeled as benign to be around 6%. Interestingly, nearly 18.4% of the pathogenic variants recorded within the ClinVar database were classified as DoS mutations.
The analysis extends to the Instability Heat Score (IHS), introduced as the average of absolute stability changes for all possible amino acid substitutions exceeding established thresholds for benign mutations. Proteins with elevated IHS are deemed fragile, indicating higher susceptibility to mutational instability, whereas those with lower scores manifest fewer adverse reactions to substitutions, demonstrating greater stability.
One of the most remarkable findings of this research is the confirmation of functional constraints influencing the degree of stability disruption among different human proteins. When proteins were classified by their functional constraints, those showing the strongest constraints had significantly lower IHS, which directly correlates to their infrequent occurrences of significant mutations.
Notably, the data indicated the HLA-B and HLA-DRB1 genes experienced DoS scores more than twice as high as those calculated via conventional loss-of-function measurement methods. These genes are well-known for their role within the immune system.
These insights challenge the traditional view of genetic disorders purely attributing causality to loss-of-function mutations. Instead, this study indicates higher frequencies of destabilizing mutations within functionally constrained proteins contribute significantly to disease pathology.
Moving forward, the research suggests screening for these types of mutations may be beneficial for early diagnosis and intervention strategies related to genetic diseases, emphasizing the need to investigate the functional ramifications of missense mutations beyond simple binary classifications of loss versus maintenance of protein function.
This study showcases the potential applications and implications of distinguishing between types of genetic variations, as biological resilience to specific mutations might aid future research and therapeutic approaches for treating genetic disorders.
Understanding the interplay of protein structure and genetic variation opens avenues for more effective genetic screening techniques, allowing for improved diagnostics and targeted treatments for individuals with genetic disorders linked to protein stability disruptions.
The research was conducted by Michael May, Amanda Chuah, Nathan Lehmann, and colleagues, providing compelling evidence of the nuanced relationship between amino acid substitution and its impact on protein stability across the human proteome.
With the steady increase of genetic diagnostic technologies, focusing on the functional consequences of genetic mutations—whether they are stabilizing or destabilizing—positions us closer to unraveling the complexity of genetic diseases.