Combinatorial in silico approach for cancer-associated 4Fe-4S protein discovery

Iron-sulfur (Fe-S) proteins play vital roles in multiple cellular processes, including mediating redox balance as well as DNA replication and repair. Given the role of Fe-S cofactors in genome maintenance, mutations in such metalloproteins could be associated with cancer. Nevertheless, only a few ca...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Tam, Winnie W L, Cheng, Michael H W, Mo, Xiaoyong, He, Bei-Bei, Ngo, Ulrike F M, Yuen, Nicholas M H, Yau, Angela Y L, Wu, Nicholas C, Tse, Edmund C M
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 13.11.2023
Subjects
Amino acid sequence
Biodegradation
Cancer
DNA biosynthesis
DNA glycosylase
DNA repair
Environmental degradation
Genomes
Growth factors
Histones
Iron-sulfur proteins
Metal ions
Mutation
Protein purification
Proteins
Proteomes
Zinc finger proteins
Online AccessGet full text

Cover

More Information
Summary:Iron-sulfur (Fe-S) proteins play vital roles in multiple cellular processes, including mediating redox balance as well as DNA replication and repair. Given the role of Fe-S cofactors in genome maintenance, mutations in such metalloproteins could be associated with cancer. Nevertheless, only a few cancer-associated Fe-S proteins have been identified. In vitro, Fe-S cluster is susceptible to degradation in oxic environment. It could also be replaced by other metal ions during protein purification, mis-labelled as zinc finger or Zn-containing proteins. In silico, bioinorganic Fe-S cluster lacks unique sequence characteristics that distinguish itself from other metal-coordination sites, making motif prediction based solely on protein sequence difficult. Thus, in this study, three traits have been employed to discover putative cancer-associated 4Fe-4S proteins. Here, we have analyzed the human proteome via a three-pronged approach: (i) the presence of a triamino acid motif, (ii) the geometric arrangements of the cysteines, and (iii) the mutations of cancer-associated cysteines. In addition to MUTYH, a known 4Fe-4S human DNA glycosylase, 21 novel proteins were discovered as potential cancer-associated 4Fe-4S proteins. While 6 receptor proteins and 3 growth factors have been identified as potential targets in this study, 5 histone lysine methyltransferases with SET domains were also predicted to contain 4Fe-4S metallocofactors. This work provides insights for rational adjustments in experimental design and novel cancer biomarker discovery.Competing Interest StatementThe authors have declared no competing interest.
DOI:10.1101/2023.11.08.566327