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Computational investigation on the impact of point mutations on the N-terminal domain of SHANK3, indicating distinct synaptopathies in Autism spectrum disorder

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Title Computational investigation on the impact of point mutations on the N-terminal domain of SHANK3, indicating distinct synaptopathies in Autism spectrum disorder
 
Creator Almaadani, Hiba Khalil
Mattaparthi, Venkata Satish Kumar
 
Subject ASD
Molecular dynamics simulation
P141A and L270M mutations
SPN-ARR domains
 
Description 527-538
SHANK3 mutations are associated with a notable 1% of autism spectrum disorder (ASD). Due to the cost and time
associated with experimental polymorphism studies, in silico investigations are deemed a rational precursor to elucidate the
role of two mutations implicated in ASD, SHANK3 P141A and SHANK3 L270M. ASD is a complex neurological
condition with diverse clinical manifestations, encompassing challenges in social interaction, communication, and repetitive
behaviors. ASD is characterized by genetic heterogeneity, converging on a limited set of molecular pathways.
Synaptopathies are one of the common neuronal processes associated with ASD, involving altered glutamatergic that may
disrupt the excitatory and inhibitory equilibrium. SHANK3 is pivotal as a scaffold protein connecting glutamate receptors to
the cytoskeleton, crucial for synaptic transmission within the post-synaptic density. We conducted a 200 ns molecular
dynamics simulation to explore SHANK3 P141A and SHANK3 L270M functional and structural consequences on the
SHANK3 protein. The P141A mutation significantly disrupted SHANK3 stabilization and caused a disturbance in
intramolecular connections between SPN and ARR domains. The alteration affected the αCaMKII binding as one of the
pivotal protein partners. On the contrary, the SHANK3 L270M mutation resulted in moderate stability conformation. The
findings underscore the intricate dynamics of SHANK3 mutations and their potential relevance to the ASD.
 
Date 2024-08-29T10:18:29Z
2024-08-29T10:18:29Z
2024-08
 
Type Article
 
Identifier 0975-0959 (Online); 0301-1208 (Print)
http://nopr.niscpr.res.in/handle/123456789/64463
https://doi.org/10.56042/ijbb.v61i9.10442
 
Language en
 
Publisher NIScPR-CSIR,India
 
Source IJBB Vol.61(09) [September 2024]