Investigating the Effects of Amino Acid Variations in Human Menin.

Carmen Biancaniello,Deborah Giordano,Serena Dotolo,Antonia D’Argenio,Bernardina Scafuri,Angelo Facchiano,Antonio D’Acierno,Roberto Tagliaferri,Anna Marabotti

doi:10.3390/molecules27051747

Abstract

Human menin is a nuclear protein that participates in many cellular processes, as transcriptional regulation, DNA damage repair, cell signaling, cell division, proliferation, and migration, by interacting with many other proteins. Mutations of the gene encoding menin cause multiple endocrine neoplasia type 1 (MEN1), a rare autosomal dominant disorder associated with tumors of the endocrine glands. In order to characterize the structural and functional effects at protein level of the hundreds of missense variations, we investigated by computational methods the wild-type menin and more than 200 variants, predicting the amino acid variations that change secondary structure, solvent accessibility, salt-bridge and H-bond interactions, protein thermostability, and altering the capability to bind known protein interactors. The structural analyses are freely accessible online by means of a web interface that integrates also a 3D visualization of the structure of the wild-type and variant proteins. The results of the study offer insight into the effects of the amino acid variations in view of a more complete understanding of their pathological role.

Highlights

Menin is a tumor suppressor protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene located on chromosome 11q13 and made up of 9 introns and 10 exons
Menin was defined as a scaffold protein that interacts directly or indirectly with various partners involved in transcriptional regulation, DNA damage repair, cell signaling, cell division, proliferation, and migration [4,5]
The study of human menin crystal structures found on RCSB PDB has highlighted that all entries have different missing residues, but residues 460–536 are missing in all of them

Summary

Introduction

Menin is a tumor suppressor protein encoded by the MEN1 gene located on chromosome 11q13 and made up of 9 introns and 10 exons. Menin contains three nuclear localization signals (NLSs) and two nuclear exit sequences (NESs) suggesting its ability to enter and exit the nucleus [1–3]. This protein is highly conserved in different animal species, but it does not share sequence similarity with other known proteins, and it does not have intrinsic enzymatic activity. Menin was defined as a scaffold protein that interacts directly or indirectly with various partners involved in transcriptional regulation, DNA damage repair, cell signaling, cell division, proliferation, and migration [4,5]. In transcription regulation, menin has been proved to suppress gene transcription by binding the AP-1 transcription factor JunD and repressing

Methods

Results

Conclusion