Pathogenic NAP57 mutations decrease ribonucleoprotein assembly in dyskeratosis congenita.

Abstract

X-linked dyskeratosis congenita (DC) is a rare bone marrow failure syndrome caused by mostly missense mutations in the pseudouridine synthase NAP57 (dyskerin/Cbf5). As part of H/ACA ribonucleoproteins (RNPs), NAP57 is important for the biogenesis of ribosomes, spliceosomal small nuclear RNPs, microRNAs and the telomerase RNP. DC mutations concentrate in the N- and C-termini of NAP57 but not in its central catalytic domain raising questions as to their impact. We demonstrate that the N- and C-termini together form the binding surface for the H/ACA RNP assembly factor SHQ1 and that DC mutations modulate the interaction between the two proteins. Pinpointing impaired interaction between NAP57 and SHQ1 as a potential molecular basis for X-linked DC has implications for therapeutic approaches, e.g. by targeting the NAP57-SHQ1 interface with small molecules.

• Authors: Petar N Grozdanov, Narcis Fernandez-Fuentes, Andras Fiser, U Thomas Meier
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 18 Issue 23 Pg. 4546-51 (Dec 01 2009) ISSN: 1460-2083 [Electronic] England
• PMID: 19734544 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carrier Proteins
• Intracellular Signaling Peptides and Proteins
• NAP57
• Nuclear Proteins
• Ribonucleoproteins
• SHQ1 protein, human

Topics

• Amino Acid Motifs
• Carrier Proteins (genetics, metabolism)
• Dyskeratosis Congenita (genetics, metabolism, pathology)
• Humans
• Intracellular Signaling Peptides and Proteins
• Molecular Conformation
• Mutation
• Nuclear Proteins (chemistry, genetics, metabolism)
• Protein Binding
• Ribonucleoproteins (genetics, metabolism)