ACBD6 Human

What is ACBD6 and what is its primary function in human cells?

ACBD6 is a ubiquitously expressed protein that plays a critical role in acylation of lipids and proteins and specifically regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs) . The protein contains an acyl-CoA binding domain (ACB) that interacts with acyl-CoA molecules and ankyrin-repeat motifs (ANK) that interact with N-myristoyltransferase .

ACBD6's primary function appears to be protecting the N-myristoylation reaction from palmitoyl-CoA and other unwanted acyl-CoA species, thereby ensuring proper N-myristoylation of target proteins . This protein modification is essential for various cellular processes, particularly in the nervous system where ACBD6 helps maintain normal neurological function .

How does ACBD6 regulate protein N-myristoylation at the molecular level?

ACBD6 regulates protein N-myristoylation through a sophisticated mechanism involving both its structural domains. The ANK module of ACBD6 directly interacts with human NMT2 (N-myristoyltransferase 2) and this interaction is both necessary and sufficient to provide protection to the enzyme . Importantly, the acyl-CoA binding domain (ACB) is not required for this protection, indicating that sequestration of competing acyl-CoAs is not the basis for NMT2 protection .

Instead, acyl-CoAs bound to the ACB domain appear to modulate the function of the ANK module, acting as positive effectors for the allosteric activation of the enzyme . Experimental evidence demonstrates that fusion of the ANK module to another acyl-CoA binding protein (ACBD1) was sufficient to confer the NMT-stimulatory property of ACBD6 to the chimera, further supporting this mechanism .

What is the relationship between ACBD6 and other ACBD family proteins?

While the search results don't provide comprehensive information about all ACBD family relationships, they do offer some insights into functional differences. Unlike ACBD5, which shows peroxisomal localization, ACBD6 does not localize to peroxisomes, and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts . This indicates distinct roles for different ACBD family proteins despite their shared acyl-CoA binding capabilities.

Other ACBD family members mentioned in the literature include ACBD1, ACBD3, ACBD4, and ACBD5, with different subcellular localizations and functions . For instance, ACBD3 is emerging as a signaling molecule, while ACBD4 and ACBD5 interact with VAP proteins to promote ER-peroxisome associations .

What clinical manifestations characterize ACBD6-related neurodevelopmental syndrome?

Bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome with complex and progressive features. Based on studies of 45 affected individuals from 28 unrelated families, the clinical manifestations include:

The most distinctive movement disorder is dystonia (94%), which frequently leads to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%) . Other movement disorders include jerky tremor in the upper limbs (63%), mild head tremor (59%), and parkinsonism/hypokinesia developing with advancing age (32%) .

What neuroimaging findings are associated with ACBD6 deficiency?

Neuroimaging studies of individuals with bi-allelic ACBD6 variants reveal characteristic brain abnormalities:

These midline brain malformations provide important diagnostic clues and insight into the neuroanatomical basis of the clinical manifestations .

How do ACBD6 mutations affect protein N-myristoylation profiles in patients?

Studies using myristic acid alkyne (YnMyr) chemical proteomics have demonstrated significant differences in N-myristoylation patterns in patient-derived fibroblasts with ACBD6 deficiency. Specifically, altered N-myristoylation was observed for 68 co-translationally and 18 post-translationally N-myristoylated proteins in these cells .

Among the affected proteins are Fus, Marcks, and Chchd-related proteins, which are implicated in various neurological diseases . This altered N-myristoylation profile provides a molecular mechanism linking ACBD6 deficiency to neurological dysfunction. Fibroblasts from individuals with neurodevelopmental disorders carrying loss-of-function mutations in the ACBD6 gene showed deficiency in protein N-myristoylation and increased sensitivity to substrate analogs competing for myristoyl-CoA binding to NMT .

What animal models have been developed to study ACBD6 function?

Researchers have generated several animal models to study ACBD6 function:

• Zebrafish acbd6 knockout: Created using CRISPR/Cas9 genome editing technology .

• Xenopus tropicalis acbd6 knockout: Also generated using CRISPR/Cas9 .

These models effectively recapitulate many clinical phenotypes observed in patients, including:

• Movement disorders

• Progressive neuromotor impairment

• Seizures

• Microcephaly

• Craniofacial dysmorphism

• Midbrain defects

• Developmental delay

• Increased mortality over time

N-myristoylation was similarly affected in these animal models as in patient fibroblasts, confirming the conserved function of ACBD6 across species and validating these models for studying the disorder .

What techniques are used to analyze N-myristoylation defects in ACBD6-deficient cells?

Several sophisticated techniques are employed to study N-myristoylation defects:

• YnMyr chemical proteomics: This technique uses myristic acid alkyne (YnMyr) to label N-myristoylated proteins, allowing for their identification and quantification. This approach has been used in both human cells and animal models to characterize the impact of ACBD6 deficiency on the N-myristoylome .

• Protein interaction studies: Methods to assess the interaction between ACBD6 (particularly its ANK domain) and NMT enzymes have been crucial for understanding the mechanism of ACBD6 function .

• Fibroblast analysis: Skin-derived fibroblasts from individuals with ACBD6 mutations provide a valuable cellular model to study the consequences of ACBD6 deficiency on N-myristoylation .

• Enzyme protection assays: Assays measuring the ability of ACBD6 to protect NMT enzymes from unwanted acyl-CoA species have been instrumental in elucidating its function .

How are ACBD6 genetic variants identified and classified in patients?

Identification and classification of ACBD6 genetic variants involve:

• Exome sequencing: This has been the primary method for identifying bi-allelic pathogenic variants in ACBD6 in affected individuals .

• International data sharing: Extensive global collaboration and data sharing among 89 clinicians and scientists from 72 institutes has been crucial for identifying affected families and establishing genotype-phenotype correlations .

• Variant classification: Variants are classified based on their predicted impact on protein function, with loss-of-function variants (18/20) predominating in the identified cases .

• Family studies: Investigation of consanguineous families (consanguinity rate of 93% in reported cases) has facilitated the identification of homozygous pathogenic variants .

What is the relationship between ACBD6 function and specific N-myristoylated proteins in neurological development?

Research has identified several N-myristoylated proteins affected by ACBD6 deficiency that may contribute to the neurological manifestations:

• Fus (Fused in Sarcoma): An RNA-binding protein implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Altered N-myristoylation of Fus in ACBD6-deficient cells may contribute to neurodegeneration .

• Marcks (Myristoylated Alanine-Rich C-Kinase Substrate): A protein involved in cell signaling and cytoskeletal regulation with important roles in neuronal development and plasticity .

• Chchd-related proteins: Mitochondrial proteins implicated in various neurological diseases, suggesting that mitochondrial dysfunction may contribute to the pathogenesis of ACBD6-related disorders .

The precise mechanisms by which altered N-myristoylation of these proteins leads to specific neurological manifestations require further investigation, but these findings provide important clues to the molecular pathogenesis.

How does phosphorylation affect ACBD6 function in acyl-CoA binding and protein interaction?

While detailed information about ACBD6 phosphorylation is limited in the search results, there is mention that phosphorylation of two serine residues of the acyl-CoA binding domain of human ACBD6 improves ligand binding capacity and prevents competition by unbound acyl-CoA . This suggests that post-translational modifications of ACBD6 itself can regulate its function and potentially modulate N-myristoylation efficiency in response to cellular signals.

The relationship between phosphorylation status and ACBD6's interaction with NMT enzymes represents an important area for future research, as it may provide insights into the regulation of N-myristoylation under different physiological conditions.

What is the current understanding of genotype-phenotype correlations in ACBD6-related disorders?

The identification of 45 affected individuals from 28 unrelated families provides a substantial cohort for such analysis, but more research is needed to determine whether specific variants correlate with particular clinical manifestations or disease severity. The high rate of consanguinity (93%) in the reported families suggests that many affected individuals carry homozygous variants, which may influence the phenotypic presentation .

What therapeutic approaches might be developed for ACBD6-related disorders?

While the search results don't directly address therapeutic approaches, understanding the molecular mechanisms of ACBD6 function suggests several potential strategies:

• N-myristoylation enhancement: Developing compounds that can enhance or restore N-myristoylation of specific target proteins affected in ACBD6 deficiency.

• Gene therapy: Given that most patients have loss-of-function mutations, gene replacement strategies could potentially restore ACBD6 function.

• Targeted symptom management: Based on the predominant movement disorders (dystonia, tremor, parkinsonism), therapies targeted at these specific symptoms might improve quality of life.

• Animal model drug screening: The established zebrafish and Xenopus models provide platforms for screening potential therapeutic compounds.

Further research into the specific downstream effects of ACBD6 deficiency will be crucial for developing targeted therapies.

How might insights from ACBD6 research contribute to understanding more common neurological disorders?

The study of ACBD6-related disorders provides valuable insights into the role of N-myristoylation in neurological function. Several connections to more common disorders can be identified:

• Parkinson's disease: The development of parkinsonism in older patients with ACBD6 deficiency suggests shared pathophysiological mechanisms with idiopathic Parkinson's disease .

• Dystonia: The high prevalence of dystonia in ACBD6-related disorders may provide insights into the molecular basis of primary dystonia syndromes.

• Neurodevelopmental disorders: Understanding how ACBD6 deficiency affects brain development could illuminate mechanisms relevant to more common neurodevelopmental conditions.

The altered N-myristoylation of proteins like Fus, which is implicated in ALS and frontotemporal dementia, suggests that disrupted N-myristoylation may contribute to neurodegenerative processes more broadly .