Pathogenic NAP57 mutations decrease ribonucleoprotein assembly in dyskeratosis congenita.
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.
Grozdanov
Petar N
PN
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Fernandez-Fuentes
Narcis
N
Fiser
Andras
A
Meier
U Thomas
UT
D020816:Amino Acid Motifs; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008968:Molecular Conformation; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C107170:NAP57; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; C542388:SHQ1 protein, human