Publications

Authors:

Yousaf, Muhammad Abrar; Meli, Massimiliano; Colombo, Giorgio; Savoia, Anna; Pastore, Annalisa

Title:

A computational study of the fold and stability of cytochrome c with implications for disease

Year:

2025

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

Elettronico

Referee:

Sì

Name of journal:

INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

ISSN of journal:

0141-8130

N° Volume:

308

Number or Folder:

Pt. 2

:

-Attuale :ELSEVIER SCIENCE BV, PO BOX 211, AMSTERDAM, NETHERLANDS, 1000 AE -Butterworth Heinemann Publishers:Linacre House Jordan Hill, Oxford OX2 8DP United Kingdom:011 44 1865 314569, EMAIL: bhmarketing@repp.co.uk, INTERNET: http://www.laxtonsprices.co.uk, Fax: 011 44 1865 314569

Page numbers:

1-18

Keyword:

Cytochrome c; Molecular dynamics simulation; Mutations; Peroxidase activity; Thrombocytopenia 4

Short description of contents:

Cytochrome c (Cyt-c), encoded by the CYCS gene, is crucial for electron transport, peroxidase activity, and apoptosis. Mutations in CYCS cause thrombocytopenia 4, 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 the mechanisms causing reduced platelet production and increased apoptosis are unclear. This study investigates clinically-related Cyt-c variants using an integrated bioinformatics approach. Our findings reveal that all variants are at evolutionarily conserved sites, potentially disrupting Cyt-c function and contributing to disease phenotypes. Specific variants are predicted to affect phosphorylation (T20I, V21G, Y49H), and ubiquitination (G42S, A52T, A52V, T103I). Molecular dynamics simulations (500 ns) revealed significant structural differences from the wild-type protein, with mutants showing reduced stability and increased unfolding and flexibility, particularly in the Ω-loops. These changes result in the displacement of the Ω-loops away from the heme iron, weakening critical hydrogen bonds and consequently opening the heme active site. This open conformation may enhance accessibility to small molecules such as H₂O₂, thereby promoting peroxidase activity, which may enhance apoptosis and likely impact megakaryopoiesis and platelet homeostasis in THC4.

Web page:

https://doi.org/10.1016/j.ijbiomac.2025.142336

Product ID:

145012

Handle IRIS:

11562/1159309

Last Modified:

May 28, 2025

Bibliographic citation:

Yousaf, Muhammad Abrar; Meli, Massimiliano; Colombo, Giorgio; Savoia, Anna; Pastore, Annalisa, A computational study of the fold and stability of cytochrome c with implications for disease «INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES» , vol. 308 , n. Pt. 2 , 2025 , pp. 1-18

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