Novel high-risk missense mutations identification in FAT4 gene causing Hennekam syndrome and Van Maldergem syndrome 2 through molecular dynamics simulation

Shinwari, Khyber; Rehman, Hafiz Muzzammel; Xiao, Ningkun; Liu, Guojun; Khan, Muhammad Ajmal; Bolkov, Mikhail A.; Tuzankina, Irina A.; Черешнев, В. А.

doi:10.1016/j.imu.2023.101160

Cited by 6 publications

(2 citation statements)

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“…PTMs refer to the chemical modifications that proteins undergo after translation, including methylation, phosphorylation, ubiquitylation, glycosylation, acetylation, and several others. PTMs play a pivotal role in the regulation of protein structures and functions, proving essential across various pathways, including cell signaling and protein-protein interactions, as well as numerous biological processes [53,54]. Mutations at or near the site of these modifications could impact their function, stability, localization, and interaction with other molecules.…”

Section: Predicting the Effects Of Ptmsmentioning

confidence: 99%

“…Heme ligation remains the same both in the ferric and ferrous forms of Cyt-c. The protein fold comprises five α-helices connected by three so-called for historic reasons Ω-loop regions, namely distal (residues 72-86), central (residues [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] and proximal (residues 13-29 and 28-40) Ω-loops [5][6][7]. These are non-regular protein structural motifs that consist of loops of six or more amino acid residues (Fetrow, 1995).…”

Section: Introductionmentioning

confidence: 99%

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A comprehensive guide through the fold and stability of cytochrome c with implications for disease

Yousaf,

Savoia,

Pastore

2024

Preprint

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Cytochrome c (Cyt-c), encoded by CYCS gene, is crucial for electron transport, peroxidase activity, and apoptosis. Mutations in CYCS can cause thrombocytopenia 4 (THC4), a disorder with low platelet counts. We have, for instance, recently described six Italian families with five different heterozygous missense CYCS variants. These mutations likely enhance peroxidase and apoptotic activities, yet mechanisms causing reduced platelet production and increased apoptosis are unclear. This study investigates all clinically important Cyt-c variants using an integrated bioinformatics approach. Our findings reveal that all variants are at evolutionarily conserved sites, likely disrupting Cyt-c function and contributing to disease phenotypes. Specific variants likely affect phosphorylation (T20I, V21G, Y49H), ubiquitination (G42S, A52T, A52V), and glycosylation (H27Y, N32H, L33V, G42S). Cyt-c variants may influence the function of interacting genes and proteins involved in apoptosis and mitochondrial function. Molecular dynamics simulations reveal significant structural differences from the wild-type, with mutants showing reduced stability and increased flexibility, particularly in the omega loops. These changes weaken hydrogen bonds and increase distances between key residues, opening the heme active site. This open conformation likely enhances accessibility to small molecules such as H2O2, thereby promoting peroxidase activity, which may enhance apoptosis and likely impact megakaryopoiesis and platelet homeostasis in THC4.

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Section: Predicting the Effects Of Ptmsmentioning

confidence: 99%